WO2009082437A2 - Selective androgen receptor modulators (sarms) and uses thereof - Google Patents

Selective androgen receptor modulators (sarms) and uses thereof Download PDF

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Publication number
WO2009082437A2
WO2009082437A2 PCT/US2008/013657 US2008013657W WO2009082437A2 WO 2009082437 A2 WO2009082437 A2 WO 2009082437A2 US 2008013657 W US2008013657 W US 2008013657W WO 2009082437 A2 WO2009082437 A2 WO 2009082437A2
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WO
WIPO (PCT)
Prior art keywords
compound
disease
androgen receptor
androgen
syndrome
Prior art date
Application number
PCT/US2008/013657
Other languages
English (en)
French (fr)
Other versions
WO2009082437A3 (en
WO2009082437A9 (en
Inventor
Lin Zhi
Original Assignee
Ligand Pharmaceuticals Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ligand Pharmaceuticals Incorporated filed Critical Ligand Pharmaceuticals Incorporated
Priority to ES08865188T priority Critical patent/ES2413504T3/es
Priority to CN200880127182.1A priority patent/CN101945853B/zh
Priority to BRPI0821090A priority patent/BRPI0821090B8/pt
Priority to US12/734,993 priority patent/US8354446B2/en
Priority to SI200830973T priority patent/SI2222636T1/sl
Priority to JP2010539438A priority patent/JP5539221B2/ja
Priority to EP20080865188 priority patent/EP2222636B1/en
Priority to DK08865188T priority patent/DK2222636T3/da
Priority to CA2709677A priority patent/CA2709677C/en
Priority to PL08865188T priority patent/PL2222636T3/pl
Priority to MX2010006972A priority patent/MX2010006972A/es
Priority to TW97148899A priority patent/TWI437003B/zh
Priority to CL2008003825A priority patent/CL2008003825A1/es
Priority to ARP080105633A priority patent/AR092284A1/es
Publication of WO2009082437A2 publication Critical patent/WO2009082437A2/en
Publication of WO2009082437A3 publication Critical patent/WO2009082437A3/en
Publication of WO2009082437A9 publication Critical patent/WO2009082437A9/en
Priority to US13/694,063 priority patent/US8748633B2/en
Priority to HRP20130552AT priority patent/HRP20130552T1/hr
Priority to US14/263,237 priority patent/US9139520B2/en
Priority to US14/827,228 priority patent/US9675583B2/en
Priority to US15/590,884 priority patent/US10106500B2/en
Priority to US16/148,798 priority patent/US10730831B2/en
Priority to US16/983,617 priority patent/US11358931B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • SARM selective androgen receptor modulator
  • IRs intracellular receptors
  • steroid receptors such as androgen receptors, estrogen receptors, mineralo- corticoid receptors, and progesterone receptors.
  • Gene regulation by such receptors typically involves binding of an IR by a ligand.
  • a ligand binds to an IR, forming a receptor/ligand complex.
  • a receptor/ligand complex can then translocate to the nucleus of a cell, where it binds to the DNA of one or more gene regulatory regions. Once bound to the DNA of a particular gene regulatory region, a receptor/ligand complex can modulate the production of the protein encoded by that particular gene.
  • an androgen receptor/ligand complex regulates expression of certain proteins.
  • an androgen receptor/ligand complex can interact directly with the DNA of a particular gene regulatory region or with other transcription factors. In certain instances, such interactions result in modulation of transcriptional activation.
  • Androgen therapy has been used to treat a variety of male disorders such as reproductive disorders and primary or secondary male hypogonadism.
  • a number of natural or synthetic AR agonists have been investigated for the treatment of musculoskeletal disorders, such as bone disease, hematopoietic disorders, neuromuscular disease, rheumatological disease, wasting disease, and for hormone replacement therapy (HRT), such as female androgen deficiency.
  • AR antagonists such as flutamide and bicalutamide, are used to treat prostate cancer.
  • the effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration.
  • potential side effects of androgen therapy for women include acne, weight gain, excess facial and body hair, permanent lowering of the voice, and adverse lipid changes.
  • adverse effects can include disordered sleep and breathing, polycythemia, and repression of high density lipoprotein.
  • Non-steroidal Selective Androgen Receptor Modulators or SARMs are non-steroidal Selective Androgen Receptor Modulators.
  • non-steroidal SARMs display therapeutic benefit but generally do not display adverse androgenic effects, such as prostate enlargement, acne, hirsutism, virilization and masculinization.
  • the compounds selectively modulate (agonize or antagonize) the function of the AR, such as in a tissue-selective manner, to produce the effects of androgens without or with reduced negative or undesired androgenic properties.
  • agonists of androgen receptor are Among the compounds provided herein are antagonists of androgen receptor.
  • compounds provided herein are androgen receptor partial agonists.
  • tissue specific selective androgen receptor modulators are tissue specific selective androgen receptor modulators. They can be used for oral testosterone replacement therapy. Compounds provided herein display agonist activity with EC 50 values generally less than 1 micromolar. Compounds provided herein display antagonist activity with IC 50 values generally less than 2 micromolar. SARMs provided herein generally target anabolic tissue, such as connective tissue, including bone and muscle, and can be used to increase the mass of a connective tissue in a subject and to reverse connective tissue loss in a subject.
  • disorders that can be treated are muscle wasting, cachexia, frailty and osteoporosis and other muscle and bone disorders, including those enumerated below.
  • R 1 is halogen, pseudohalogen, optionally substituted lower alkyl, optionally substituted haloalkyl or NO 2 , particularly lower haloalkyl or halogen, and in particular is CF 3 , F, or Cl;
  • R 2 is hydrogen, halogen, pseudohalogen, optionally substituted lower alkyl or optionally substituted lower haloalkyl, particularly hydrogen or methyl;
  • R 3 is hydrogen, halogen, pseudohalogen, optionally substituted lower alkyl or optionally substituted lower haloalkyl, particularly hydrogen or lower alkyl, and in particular hydrogen or methyl;
  • R 4 is halogen or lower haloalkyl, particularly CF 3 or halogen, and in particular Cl or CF 3 ;
  • R 5 is lower alkyl or lower haloalkyl, particularly Ci to C 4 alkyl or Ci to C 4 haloalkyl, and in particular methyl, ethyl or CF 3 .
  • the compounds provided herein exhibit tissue selective androgen receptor agonist activity. In some embodiments, the compounds provided herein exhibit tissue selective androgen receptor antagonist activity. In some embodiments, the compounds provided herein are androgen receptor selective binding compounds.
  • Compounds provided herein are effective for treating one or more androgen receptor mediated diseases or conditions. Such conditions and diseases include those caused by androgen deficiency and/or those that can be ameliorated by androgen administration. In certain embodiments, compounds provided herein are effective for treating one or more diseases or conditions responsive to an androgen receptor agonist. In certain embodiments, compounds provided herein are effective in treating one or more conditions whose etiology involves hypoactivity or subsensitivity of androgen receptor. In other embodiments, compounds provided herein are effective for treating one or more diseases or conditions responsive to an androgen receptor antagonist. In other embodiments, compounds provided herein are effective in treating one or more conditions whose etiology involves hyperactivity of androgen receptor.
  • the compounds provided herein can exhibit AR agonist activity and can be used to treat conditions that are caused by androgen deficiency or hypoactivity or subsensitivity of androgen receptor, or that can be ameliorated by androgen replacement or are responsive to treatment with an AR agonist.
  • Such conditions include, but not limited to, aging skin; Alzheimer's disease; anemias, such as for example, aplastic anemia; anorexia; arthritis, including inflammatory arthritis, rheumatoid arthritis, osteoarthritis and gout; arteriosclerosis; atherosclerosis; bone disease, including metastatic bone disease; bone damage or fracture, such as by accelerating bone fracture repair and/or stimulation of osteoblasts and/or stimulation of bone remodeling and/or stimulation of cartilage growth; distraction osteogenesis; reduced bone mass, density or growth; bone weakening, such as induced by glucocorticoid administration; musculoskeletal impairment (e.g., in the elderly); cachexia; cancer, including breast cancer and osteosarcoma; cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); cardiomyopathy; catabolic side effects of glucocorticoids; Crohn's disease; growth retardation in connection with Crohn's disease; short
  • erectile dysfunction decreased sex drive, sexual well-being, decreased libido
  • physiological short stature including growth hormone deficient children and short stature associated with chronic illness and growth retardation associated with obesity
  • tooth damage such as by acceleration of tooth repair or growth
  • thrombocytopenia vaginal dryness
  • vaginal dryness atrophic vaginitis
  • ventricular dysfunction wasting, including wasting secondary to fractures and wasting in connection with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic state (e.g., coma), eating disorders (e.g., anorexia), chemotherapy, multiple sclerosis or other neurodegenerative disorders.
  • COPD chronic obstructive pulmonary disease
  • the compounds provided herein exhibit AR agonist activity and can be used to stimulate pulsatile growth hormone release; in hormone replacement therapy, such as female androgen deficiency and male androgen decline; to improve bone strength, muscle strength and tone; to reduce subcutaneous fat in a subject; to enhance bone and muscle performance/strength; to increase athletic performance; to attenuate or reverse protein catabolic responses following trauma (e.g., reversal of the catabolic state associated with surgery, congestive heart failure, cardiac myopathy, burns, cancer, COPD); to improve sleep quality and/or correct the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency; and to treat age related decreased testosterone levels in men.
  • hormone replacement therapy such as female androgen deficiency and male androgen decline
  • to improve bone strength, muscle strength and tone to reduce subcutaneous fat in a subject
  • to enhance bone and muscle performance/strength to increase athletic performance
  • the compounds provided herein can exhibit AR antagonist activity and can be used to treat conditions whose etiology involves hyperactivity of androgen receptor or that are responsive to treatment with an AR antagonist.
  • Such conditions include, but are not limited to, acanthosis nigricans, acne, adrenal hyper- androgenism, androgenetic alopecia (male-pattern baldness), adenomas and neoplasias of the prostate (e.g., advanced metastatic prostate cancer), benign prostate hyperplasia, cancer (e.g., cancer of the breast, bladder, endometrium, lung (non-small cell lung cancer), pancreas, prostate, including androgen dependent prostate cancer, and skin ); bulimia nervosa; chronic fatigue syndrome (CFS); chronic myalgia; acute fatigue syndrome; contraception; counteracting preeclampsia, eclampsia of pregnancy and preterm labor; delayed wound healing; erythrocytosis; gestational diabetes; hirsu
  • compounds provided herein are effective for treating prostate cancer. In certain embodiments, compounds provided herein are effective for treating androgen dependant prostate cancer. In certain embodiments, compounds provided herein are effective for treating androgen independent prostate cancer. In certain embodiments, compounds provided herein are effective for treating androgen independent androgen receptor dependent prostate cancer.
  • the methods of treatment are practiced by administering to the subject a compound provided herein.
  • provided herein are methods for treating a condition responsive to androgen receptor modulation in a subject by identifying a subject in need of such treatment and administering to the subject a compound provided herein.
  • the methods provided herein are for treating a disease or condition responsive to an androgen receptor agonist.
  • the methods provided herein are for treating a condition responsive to an androgen receptor antagonist.
  • provided herein are methods for modulating an activity of an androgen receptor by contacting an androgen receptor with at least one compound provided herein.
  • the androgen receptor is in a cell.
  • the modulation is agonizing the receptor.
  • the modulation is antagonizing the receptor.
  • provided herein are methods for identifying a compound that is capable of modulating an activity of an androgen receptor by contacting a cell expressing an androgen receptor with a compound provided herein and monitoring an effect of the compound upon the cell.
  • methods of contraception in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to provide contraception.
  • the compound is coadministered with an androgen selected from among testosterone, 19-nortestosterone, 7of-methyl-l 9-nortestosterone and 5 ⁇ -dihydro-testosterone.
  • the subject is male and a compound of formula I, II or III is administered in an amount effective to suppress sperm production in the subject, thereby effecting contraception in the subject.
  • the compounds provided herein inhibit spermatogenesis in a subject.
  • the subject is female and a compound of formula I, II or III is administered in an amount effective to provide contraception in the subject.
  • provided herein are methods for providing hormone therapy.
  • the methods include administering to the subject a compound of formula I, II or III, in an amount effective to modulate androgen receptor activity, and thereby effect a change in an androgen-dependent condition.
  • the compound is an androgen receptor agonist.
  • the compound is an androgen receptor antagonist.
  • provided herein are methods for treating cancer in a subject, comprising administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat cancer in the subject.
  • the cancer is selected from among breast cancer, colorectal cancer, gastric carcinoma, glioma, head and neck squamous cell carcinoma, skin cancer, papillary renal carcinoma, leukemia, lymphoma, Li- Fraumeni syndrome, malignant pleural mesothelioma, melanoma, multiple myeloma, non-small cell lung cancer, synovial sarcoma, thyroid carcinoma, transitional cell carcinoma of urinary bladder, and prostate cancer.
  • the compound is administered in an amount effective to kill the cancerous cells. In some embodiments, the compound is administered in an amount effective to inhibit growth and/or metastasis of the cancer. In some embodiments, the compound is coadministered with one or more other therapeutic agents selected from among antiproliferative agents, anti-tumor agents, adrenocorticosteroids, progestins, estrogens, antiestrogens, radionuclides, toxins and cytotoxic drugs, chemotherapy agents, photodynamic therapy dyes and antibiotics or combinations thereof.
  • one or more other therapeutic agents selected from among antiproliferative agents, anti-tumor agents, adrenocorticosteroids, progestins, estrogens, antiestrogens, radionuclides, toxins and cytotoxic drugs, chemotherapy agents, photodynamic therapy dyes and antibiotics or combinations thereof.
  • kits for treating prostate cancer in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat prostate cancer in the subject.
  • the prostate cancer is androgen dependant prostate cancer.
  • the prostate cancer is androgen independent prostate cancer.
  • the prostate cancer is androgen independent, but androgen receptor dependant prostate cancer.
  • the compound is administered to the subject in an amount effective to kill the cancerous cells.
  • the compound is administered to the subject in an amount effective to inhibit the growth and/or metastasis of the prostate cancer cells.
  • the compound is coadministered with another therapeutic agent selected from among fiutamide, a toxin, bicalutamide, nilutamide, an anti-tumor agent, a cytotoxic drug, a radio-nuclide and combinations thereof.
  • another therapeutic agent selected from among fiutamide, a toxin, bicalutamide, nilutamide, an anti-tumor agent, a cytotoxic drug, a radio-nuclide and combinations thereof.
  • the compound and/or another therapeutic agent if present, is selectively targeted to react with prostate cancer cells by conjugating the compound and/or therapeutic agent to a prostate tumor antigen.
  • provided herein are methods of delaying the progression of prostate cancer in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to delay the progression of prostate cancer in the subject.
  • methods of improving athletic performance in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to improve athletic performance in the subject.
  • provided herein are methods of increasing muscle performance, muscle size and/or muscle strength in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to increase muscle performance, muscle size and/or muscle strength in a subject.
  • methods of treating, preventing, suppressing, inhibiting or reducing the incidence of muscle wasting in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to treat, prevent, suppress, inhibit or reduce the incidence of a muscle wasting in the subject.
  • the muscle wasting is caused by a condition selected from among andropause, spinal muscular atrophies, muscular dystrophies (e.g., Duchenne, Myotonic and Becker), myasthenia gravis, cachexias such as AIDS cachexia, cardiac cachexia, and cancer cachexia, cancer, Chronic Obstructive Pulmonary Disease (COPD), emphysema, diabetes, HIV infection, acquired immunodeficiency syndrome (AIDS), sepsis, tuberculosis, renal failure, heart failure, cardiomyopathy, bed rest, disuse, inactivity, microgravity, malnutrition, sarcopenia, aging and frailty (e.g., see Lynch et al, Pharmacology & Therapeutics 113(3): 461-487 (2007)).
  • COPD Chronic Obstructive Pulmonary Disease
  • emphysema diabetes
  • HIV infection HIV infection
  • AIDS acquired immunodeficiency syndrome
  • sepsis tuberculosis
  • renal failure e.
  • provided herein are methods of treating a neurodegenerative disease or disorder in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to treat the neurodegenerative disease or disorder in the subject.
  • the neurodegenerative disorder is Alzheimer's disease.
  • provided herein are methods for preventing the onset or delaying the progression of Alzheimer's disease in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to prevent the onset or delay the progression of Alzheimer's disease in the subject.
  • the compound is co-administered with an effective amount of a compound that inhibits the formation or release of /3-amyloid.
  • provided herein are methods for treating cognitive impairment in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to treat cognitive impairment in the subject.
  • kits for treating depression in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to treat depression in the subject.
  • kits for treating one or more postmenopausal conditions in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to treat one or more postmenopausal conditions in the subject.
  • the postmenopausal condition is selected from among loss of libido, decreased sexual activity, diminished feelings of physical well-being, fatigue and hot flashes.
  • the compound is co-administered with another therapeutic agent selected from among estrone, 2- hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone, 15-ohydroxy-estrone, 1 ⁇ -ct- hydroxyestrone, 16-/?-hydroxyestrone, estradiol (17-/3-estradiol), 2-hydroxy-estradiol, 2-methoxy-estradiol, 4-hydroxy-estradiol, 16-oxoestradiol, estriol, 16-epiestriol and 17-epiestriol and combinations thereof.
  • another therapeutic agent selected from among estrone, 2- hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone, 15-ohydroxy-estrone, 1 ⁇ -ct- hydroxyestrone, 16-/?-hydroxyestrone, estradiol (17-/3-estradiol), 2-hydroxy-estradiol, 2-methoxy-estradiol, 4-hydroxy-estradiol, 16-oxoestradi
  • the compound is coadministered with another therapeutic agent selected from among estradiol valerate, estrone, estrone sulfate, an estrone sulfate piperazine salt or an ester thereof, a synthetic estrogen and combinations thereof.
  • another therapeutic agent selected from among estradiol valerate, estrone, estrone sulfate, an estrone sulfate piperazine salt or an ester thereof, a synthetic estrogen and combinations thereof.
  • the compound is co-administered with another therapeutic agent selected from among alendronate, calcitonin, clodronate, clomiphene, clomiphene citrate, clonidine, conjugated estrogen, natural or synthetic estrogen, ethinyl estradiol, estradiol, enclomiphene, enclomiphene citrate, etidronate, ibandronate, medroxy-progesterone acetate, megestrol acetate, norethindrone acetate, pamidronate, progesterone, risedronate, tiludronate, zuclomiphene, zuclomiphene citrate and combinations thereof.
  • another therapeutic agent selected from among alendronate, calcitonin, clodronate, clomiphene, clomiphene citrate, clonidine, conjugated estrogen, natural or synthetic estrogen, ethinyl estradiol, estradiol, enclomiphene, enc
  • provided herein are methods of improving the lipid profile in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to affect the lipid profile in the subject.
  • methods of reducing circulating lipid levels in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to reduce circulating lipid levels in the subject.
  • the compound is co-administered with a therapeutic agent selected from among /3-hydroxy-/3-methylbutyric acid, lactoferrin, cholestyramine, colestipol, colesevelam, nicotinic acid, one or more fibric acids (e.g., gemfibrozil, fenofibrate and clofibrate) and one or more HMG-CoA reductase inhibitors (lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerivastatin) and combinations thereof.
  • a therapeutic agent selected from among /3-hydroxy-/3-methylbutyric acid, lactoferrin, cholestyramine, colestipol, colesevelam, nicotinic acid, one or more fibric acids (e.g., gemfibrozil, fenofibrate and clofibrate) and one or more HMG-CoA reductase inhibitors (lovastat
  • kits for treating atherosclerosis, a cardiovascular disorder, a cerebrovascular disorder, a peripheral vascular disorder, and/or an intestinal vascular disorder in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the atherosclerosis, cardiovascular disorder, cerebrovascular disorder, peripheral vascular disorder, and/or intestinal vascular disorder in the subject.
  • the compound is co-administered with a selective estrogen receptor modulator (SERM) compound.
  • SERM selective estrogen receptor modulator
  • provided herein are methods of treating osteoporosis, osteopenia, glucocorticoid-induced osteoporosis or bone fracture in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the osteoporosis, osteopenia, glucocorticoid-induced osteoporosis or bone fracture in the subject.
  • the compound is co-administered with an effective amount of at least one other therapeutic agent selected from among estrogen, estrogen derivatives, progestin, progestin derivatives, a bisphosphonate, an anti-estrogen, a selective estrogen receptor modulator (SERM), an ⁇ vft integrin receptor antagonist, a cathepsin inhibitor, a proton pump inhibitor, a PPAR ⁇ inhibitor, calcitonin, osteoprotegerin and combinations thereof.
  • at least one other therapeutic agent selected from among estrogen, estrogen derivatives, progestin, progestin derivatives, a bisphosphonate, an anti-estrogen, a selective estrogen receptor modulator (SERM), an ⁇ vft integrin receptor antagonist, a cathepsin inhibitor, a proton pump inhibitor, a PPAR ⁇ inhibitor, calcitonin, osteoprotegerin and combinations thereof.
  • kits for increasing the strength or mass of bone of a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increase the strength or mass of a bone in the subject.
  • kits for promoting bone formation in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to promote bone formation in the subject.
  • kits for treating a hematopoietic disorder in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the hematopoietic disorder in the subject.
  • the hematopoietic disorder is selected from among anemia, leukemia, and hematopoietic conditions caused by bone marrow transplantation or chemotherapy or radiation therapy.
  • provided herein are methods of increasing the number of red blood cells in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increase the number of red blood cells in the subject.
  • methods of treating anemia, thrombocytopenia or neutropenia in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat anemia, thrombocytopenia or neutropenia in the subject.
  • the compound is co-administered with a therapeutically effective amount of at least one hematopoietic cytokine.
  • the hematopoietic cytokine is selected from among erythropoietin, granulocyte-colony stimulating factor, granulocyte-macrophage- colony stimulating factor, interleukin-1, interleukin-3, interleukin-4, interleukin-5, interleukin-7, interleukin-9, interleukin-11, macrophage-colony stimulating factor, stem cell factor and thrombopoietin.
  • kits for increasing serum erythropoietin (EPO) levels in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increasing serum EPO levels in the subject.
  • EPO erythropoietin
  • provided herein are methods of preventing and/or treating obesity or an obesity-related condition or disease in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to prevent and/or treat obesity or an obesity-related condition or disease in the subject.
  • provided herein are methods of treating abdominal adiposity in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof that is an AR agonist, in an amount effective to treat abdominal adiposity in the subject.
  • provided herein are methods of treating abdominal obesity in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof that is an AR antagonist, in an amount effective to treat abdominal obesity in the subject.
  • methods of treating insulin resistance in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat insulin resistance in the subject.
  • kits for treating type 2 diabetes in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat type 2 diabetes in the subject.
  • the compound is co-administered with an effective amount of an anti-diabetic drug, such as, but not limited to, thiazolidinedione-type drugs such as pioglitazone or rosiglitazone, sulfonylurea-type drugs, such as chlorpropamide, glimepiride, glipizide, glyburide or tolbutamide, a biguanide-type drug such as metformin, exenatide, acarbose, repaglinide, nateglinide, tolazamide or combinations thereof.
  • an anti-diabetic drug such as, but not limited to, thiazolidinedione-type drugs such as pioglitazone or rosiglitazone, s
  • provided herein are methods of treating arterial hypertension, hyper-insulinaemia, hyperglycemia or dyslipidemia in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat arterial hypertension, hyper-insulinaemia, hyperglycemia or dyslipidemia in the subject.
  • kits for the treatment or prevention of an arthritic condition or inflammatory disorder in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat or prevent the arthritic condition or inflammatory disorder in the subject.
  • the arthritic condition or inflammatory disorder is selected from among osteoarthritis, Behcet's disease, bursitis, tendonitis, CPPD deposition disease, carpal tunnel syndrome, Ehlers-Danlos syndrome, fibromyalgia, gout, infectious arthritis, inflammatory bowel disease, juvenile arthritis, lupus erythematosus, Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis imperfecta, osteonecrosis, polyarteritis, polymyalgia rheumatica, psoriatic arthritis, Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, Reiter's syndrome, rheumatoid arthritis, scleroderma and Sjogren's syndrome.
  • provided herein are methods for the treatment or prevention of osteoarthritis in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat or prevent osteoarthritis in the subject.
  • the compound is co-administered with corticosteroids, gold treatment, methotrexate, aspirin, NSAIDs, COX-2 inhibitors and DMARDs (Disease-Modifying Anti-Rheumatic Drugs).
  • provided herein are methods of treating sexual dysfunction in a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat sexual dysfunction in the subject.
  • the sexual dysfunction is male erectile dysfunction.
  • the sexual dysfunction is impotence.
  • provided herein are methods of increasing the libido of a subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increase the libido of the subject.
  • provided herein are methods of treating a condition related to androgen decline in a male subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the condition related to androgen decline in the subject.
  • the condition is selected from among fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostate hyperplasia, anemia, alterations in mood and cognition, and prostate cancer.
  • provided are methods of treating sarcopenia in a subject.
  • provided herein are methods of treating a condition related to androgen deficiency in a female subject.
  • the methods include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the condition related to androgen decline in the subject.
  • the condition is selected from among sexual dysfunction, decreased sexual libido, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer.
  • kits for treating a disease in a subject include administering to the subject a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the disease, wherein the disease is selected from among angina, coronary artery disease, arteriosclerosis, atherosclerosis, obesity, diabetes, syndrome X, glucose intolerance, insulin resistance, hypercholesterolemia, hyperlipoproteinemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, glaucoma, hypertension, hypertriglyceridemia, renal disease, thrombosis, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, diabetic dyslipidemia, mixed dyslipidemia and nonalcoholic fatty liver disease.
  • the disease is selected from among angina, coronary artery disease, arteriosclerosis, atherosclerosis, obesity, diabetes, syndrome X, glucose intolerance, insulin resistance, hypercholesterolemia, hyperlipoproteinemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, glaucoma, hyper
  • compositions formulated for administration by an appropriate route and means including effective concentrations of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutically acceptable derivatives thereof, that deliver amounts effective for the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders that are modulated or otherwise affected by androgen receptor activity, or in which androgen receptor activity is implicated, also are provided.
  • the effective amounts and concentrations are effective for ameliorating any of the symptoms of any of the diseases or disorders.
  • a pharmaceutical composition including: i) a physiologically acceptable carrier, diluent, and/or excipient; and ii) one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof.
  • compounds provided herein are used to detect the presence, quantity and/or state of androgen receptors in a sample, such as a cell, cell homogenates and lysates.
  • samples are obtained from a subject.
  • compounds are radio- or isotopically-labeled.
  • articles of manufacture that include packaging material, within the packaging material one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, or composition that includes one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, that is effective for modulating the activity of androgen receptor, or for treatment, prevention or amelioration of one or more symptoms of androgen receptor mediated diseases or disorders, or diseases or disorders in which androgen receptor activity is implicated, and a label that indicates that the compound or composition is used for modulating the activity of androgen receptor, or for treatment, prevention or amelioration of one or more symptoms of androgen receptor mediated diseases or disorders, or diseases or disorders in which androgen receptor activity is implicated.
  • kits which contain the compositions including the compounds described herein, a device for administration of the composition and, optionally, instructions for administration.
  • ranges and amounts can be expressed as “about” a particular value or range. “About” also includes the exact amount. Hence “about 10%” means “about 10%” and also “10%.”
  • an optionally substituted group means that the group is unsubstiruted or is substituted.
  • compositions comprising "a therapeutic agent” includes compositions with one or a plurality of therapeutic agents.
  • target receptor refers to a molecule or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is a androgen receptor.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target receptors.
  • selective binds refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor.
  • specific binding refers to binding to a target with an affinity that is at least 2, 5, 10, 25, 50, 75, 100, 150, 200, 250, 500, 1000 or more times greater than the affinity for a non-target.
  • the term "androgen receptor selective binding compound” refers to a compound that selectively interacts with an androgen receptor with a greater affinity than it with a non-androgen receptor, such as, but not limited to, a progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), retinoic acid receptor (RAR), rexinoid receptor (RXR), or peroxisome proliferator-activated receptor (PPAR).
  • PR progesterone receptor
  • ER estrogen receptor
  • GR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • RAR retinoic acid receptor
  • RXR rexinoid receptor
  • PPAR peroxisome proliferator-activated receptor
  • an androgen receptor selective binding compound binds to an androgen receptor with an affinity that is at least 5, 10, 25, 50, 75, 100, 150, 200, 250, 500, 1000 or more times greater than the affinity for a non-androgen receptor.
  • the compounds provided herein are androgen receptor selective binding compounds.
  • "treating a subject having a disease or condition” means that a compound, composition or other product provided herein is administered to the subject.
  • treat and “treating” encompass either or both responsive and prophylaxis measures, e.g., designed to inhibit, slow or delay the onset of a symptom of a disease or disorder, achieve a full or partial reduction of a symptom or disease state, and/or to alleviate, ameliorate, lessen, or cure a disease or disorder and/or its symptoms.
  • treatment also is intended to include prophylactic treatment.
  • treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Hence, treatment encompasses prophylaxis, therapy and/or cure. Treatment also encompasses any pharmaceutical use of the compositions herein.
  • therapeutic agent refers to conventional drugs and drug therapies, including vaccines, which are known to those skilled in the art.
  • amelioration of the symptoms of a particular disease or disorder by a treatment refers to any lessening, whether permanent or temporary, lasting or transient, of the symptoms that can be attributed to or associated with administration of the composition or therapeutic.
  • prevention or prophylaxis refers to methods in which the risk of developing disease or condition is reduced.
  • Prophylaxis includes reduction in the risk of developing a disease or condition and/or a prevention of worsening of symptoms or progression of a disease or reduction in the risk of worsening of symptoms or progression of a disease.
  • an effective amount of a compound or composition for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease.
  • Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective.
  • the amount can cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve a desired amelioration of symptoms.
  • therapeutically effective amount refers to an agent, compound, material, or composition containing a compound that is at least sufficient to produce a therapeutic effect.
  • An effective amount is the quantity of a therapeutic agent necessary for preventing, curing, ameliorating, arresting or partially arresting a symptom of a disease or disorder.
  • amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the compound or composition.
  • a modulator refers to a compound that alters an activity of a molecule.
  • a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule.
  • an inhibitor completely prevents one or more activities of a molecule.
  • a modulator is an activator, which increases the magnitude of at least one activity of a molecule.
  • the presence of a modulator results in an activity that does not occur in the absence of the modulator.
  • selective modulator refers to a compound that selectively modulates a target activity.
  • SARM selective androgen receptor modulator
  • target tissues e.g., muscle and/or bone
  • SARMs exhibit tissue selective androgen agonism.
  • SARMs exhibit agonistic anabolic properties and antagonistic androgenic properties in selected tissues.
  • SARMs that are AR agonists in some tissues and cause increased transcription of AR-responsive genes (e.g., muscle anabolic effect).
  • compounds are competitive inhibitors of androgens such as testosterone on the AR and thereby prevent agonistic effects of the native androgens.
  • compounds provided herein are SARMs that have agonist activity in muscle and demonstrate antagonist activity in a gonad of a subject. SARMs that demonstrate such activity can increase muscle mass and decrease fat in subjects without causing androgenic side effects, such as sebaceous gland stimulation.
  • tissue selective androgen receptor agonism refers to the ability of a SARMs compound to agonize an androgen receptor of one (or more than one) target tissue with greater affinity than it agonizes an androgen receptor of a non-target tissue.
  • tissue selective androgen receptor agonism refers to agonism of an AR of a target tissue that is at least about or 2 fold up to more than about or 500 fold, greater than the androgen receptor agonism of an androgen receptor of a non-target tissue.
  • tissue selective androgen receptor agonism refers to agonism of an AR of a target tissue that is at least 2, 5, 10, 15, 20, 25, 30, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 or more times greater than the androgen receptor agonism of an androgen receptor of a non-target tissue.
  • SARMs can exhibit agonism of an AR receptor in muscle tissue and antagonism of the AR in prostate tissue.
  • tissue selective androgen receptor antagonism refers to the ability of a SARMs compound to antagonize an androgen receptor of one (or more than one) target tissue with greater affinity than it antagonizes an androgen receptor of a non-target tissue.
  • tissue selective androgen receptor antagonism refers to antagonism of an AR of a target tissue that is at least about or 2 fold up to more than about or 500 fold, greater than the androgen receptor agonism of an androgen receptor of a non-target tissue.
  • tissue selective androgen receptor antagonism refers to antagonism of an AR of a target tissue that is at least 2, 5, 10, 15, 20, 25, 30, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 or more times greater than the androgen receptor antagonism of an androgen receptor of a non-target tissue.
  • SARMs can exhibit antagonist activity against hormone-dependent tumors while exhibiting no activity, or in some instances agonist activity, against other non- tumor tissues containing the androgen receptor.
  • the term "selectively modulates” refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity.
  • the target activity is selectively modulated by, for example about or 2 fold up to more than about or 500 fold, in some embodiments, about or 2, 5, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or more than 500 fold.
  • an "activity" of a SARMS compound provided herein refers to any activity exhibited by a selective androgen modulator. Such activities can be tested in vitro and/or in vivo and include, but are not limited to, agonism or antagonism of an androgen receptor. Activity can be assessed in vitro or in vivo using recognized assays, for example, by using the co-transfection assay. The results of such assays that indicate that a compound exhibits an activity can be correlated to activity of the compound in vivo, in which in vivo activity can be referred to as biological activity. Assays to determine functionality or activity of androgen receptor modulators, including selective androgen receptor modulator compounds, are known to those of skill in the art.
  • Exemplary assays include, but are not limited to, fluorescence polarization assay, luciferase assay and co-transfection assay.
  • the compounds provided herein are capable of modulating activity of androgen receptor in a "co-transfection” assay (also called a “cis-trans” assay), which is known in the art (see e.g., Evans et al, Science 240: 889-895 (1988); U.S. Patent Nos. 4,981,784 and 5,071,773; and Pathirana et al, "Nonsteroidal Human
  • biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test or use such activities. Thus, for purposes herein a biological activity of a selective androgen receptor modulator encompasses the agonism or antagonism of an androgen receptor.
  • the term "assess” and grammatical variations thereof, is intended to include quantitative and qualitative determination in the sense of obtaining an absolute value for the activity of a compound, and also of obtaining an index, ratio, percentage, visual or other value indicative of the level of the activity. Assessment can be direct or indirect.
  • targeting agent refers to any moiety, such as a protein or effective portion thereof, that provides specific binding to a cell surface molecule, such a cell surface receptor, which in some instances can internalize a bound conjugate or portion thereof.
  • a targeting agent also can be one that promotes or facilitates, for example, affinity isolation or purification of the conjugate; attachment of the conjugate to a surface; or detection of the conjugate or complexes containing the conjugate.
  • derivative or analog of a molecule refers to a portion derived from or a modified version of the molecule.
  • a derivative includes, but is not limited, to acid derivatives, amide derivatives, ester derivatives and ether derivatives.
  • the SARM compounds provided herein are hydrates, including hemihydrate, monohydrate, dehydrate and trihydrate.
  • disease refers to a pathological condition in an organism resulting from cause or condition including, but not limited to, infections, acquired conditions, genetic conditions, and characterized by identifiable symptoms. Diseases and disorders also include those that are caused by the absence of a compound, such as an androgen agonist.
  • patient or “subject” to be treated includes humans and or non-human animals, including mammals.
  • Mammals include primates, such as humans, chimpanzees, gorillas and monkeys; domesticated animals, such as dogs, horses, cats, pigs, goats, cows; and rodents such as mice, rats, hamsters and gerbils.
  • animal includes any animal, such as, but not limited to; primates including humans, gorillas and monkeys; rodents, such as mice and rats; fowl, such as chickens; ruminants, such as goats, cows, deer, sheep; ovine, such as pigs and other animals.
  • Non-human animals exclude humans as the contemplated animal.
  • a "combination” refers to any association between two or among more items.
  • the association can be spatial or refer to the use of the two or more items for a common purpose.
  • composition refers to any mixture of two or more products or compounds (e.g., agents, modulators, regulators, etc.). It can be a solution, a suspension, liquid, powder, a paste, aqueous or non-aqueous formulations or any combination thereof.
  • a “fluid” refers to any composition that can flow. Fluids thus encompass compositions that are in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams and other such compositions.
  • kits refers to a packaged combination, optionally including reagents and other products and/or components for practicing methods using the elements of the combination.
  • kits containing a compound provided herein and another item for a purpose including, but not limited to, administration, diagnosis, and assessment of a biological activity or property are provided. Kits optionally include instructions for use.
  • an "article of manufacture” is a product that is made and sold. As used throughout this application, the term is intended to encompass compounds of formulae I, II or III contained in articles of packaging.
  • target activity refers to a target activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.
  • conditions mediated by an androgen receptor are those in which an androgen receptor plays a role.
  • Androgen receptors are known to play a role in conditions including, for example, acne, aging skin, male-pattern baldness, sexual dysfunction, impotence, depression, wasting diseases, HIV-wasting, frailty, cognitive decline, Alzheimer's disease, sleep apnea, hirsutism, hypogonadism, premature ovarian failure, inflammatory arthritis and joint repair, osteopenia, osteoporosis, glucocorticoid-induced osteoporosis, bone fracture, bone damage following bone reconstructive surgery, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, obesity, abdominal adiposity, metabolic syndrome, type II diabetes, muscular dystrophies, periodontal disease, sarcopenia, postmenopausal symptoms in women,
  • the term “receptor mediated activity” refers any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • the term “agonist” refers to a compound, the presence of which results in an activity of a receptor that is the same as the activity resulting from the presence of a naturally occurring ligand for the receptor.
  • An agonist of the androgen receptor can bind to the androgen receptor and initiate a physiological or a pharmacological response characteristic of that receptor.
  • a "full agonist” induces full activation of the androgen receptor population at a given concentration.
  • partial agonist refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
  • a "partial agonist” is an agonist that is unable to induce maximal activation of the receptor population, regardless of the amount of compound applied.
  • antagonist refers to a compound, the presence of which results in a decrease in the magnitude of an activity of a receptor.
  • the presence of an antagonist results in complete inhibition of an activity of a receptor.
  • the compound binds to androgen receptor and blocks or inhibits the androgen-associated responses normally induced by a natural androgen receptor ligand.
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of androgen receptor activity, in an assay that measures such response. IC 50 also refers to the concentration of test compound required to decrease specific binding by 50%. IC 50 values can be determined using the log-logit (Hill) method. As used herein, EC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • pharmaceutical composition refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a subject.
  • a pharmaceutical composition includes an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical composition includes a prodrug.
  • a pharmaceutical composition includes inactive ingredients such as carriers and excipients.
  • a prodrug refers to a compound that is converted from a less active form into a corresponding more active form in vivo.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically more active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • prodrugs of the compound see, e.g., Nogrady, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392 (1985)).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference in its entirety.
  • a non-limiting example of a prodrug for use herein includes those that promote the solubility of alcohols such as by the procedures described in Mahfous, N. H. et al, J. Pharm. Pharmacol. 53: 841-848 (2001) and Bundgaard, H. et al, J. Med. Chem. 32: 2503- 2507 (1989), both of which are incorporated herein by reference in their entirety.
  • Prodrugs include compounds where hydroxy, ester, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, ester, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups within the compounds provided herein.
  • esters refers to a chemical moiety with formula -(R) n -COOR 1 , where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), a non-aromatic heterocycle, arylalkyl or heteroarylalkyl, and where n is 0 or 1.
  • Any hydroxy side chain on the compounds described herein can be esterified.
  • the procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis (3 rd ed., John Wiley & Sons, New York, N. Y. (1999)).
  • prodrug ester or "ester derivative” of the compounds disclosed herein, which are formed by the addition of any of several ester- forming groups that are hydrolyzed under physiological conditions.
  • prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • Other examples of prodrug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Prodrugs as Novel Delivery Systems", Vol. 14, A. C. S. Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987).
  • a pharmaceutically acceptable formulation refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a subject. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a subject.
  • pharmaceutically acceptable derivative refers to derivatives of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a subject, and include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof.
  • Such derivatives can be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced can be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to chloroprocaine, choline, N,N'-dibenzyl-ethylenediamine, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzyl-phenethylamine, 1 -para-chloro-benzyl-2-pyrrolidin- 1 '-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxy- methyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such
  • Exemplary pharmaceutically acceptable salts include acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, bromide, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/ diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
  • Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about or 100, or 1 to about or 10, or one to about or 2, 3 or 4, solvent or water molecules.
  • alkyl refers to straight or branched chain substituted or unsubstituted hydrocarbon groups, in one embodiment 1 to 40 carbon atoms, in another embodiment, 1 to 20 carbon atoms, in another embodiment, 1 to 10 carbon atoms.
  • the expression “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms.
  • An alkyl group can be a "saturated alkyl,” meaning that it does not contain any alkene or alkyne groups and in certain embodiments, alkyl groups are optionally substituted.
  • An alkyl group can be an "unsaturated alkyl,” meaning that it contains at least one alkene or alkyne group.
  • alkyl group that includes at least one carbon-carbon double bond also is referred to by the term "alkenyl,” and in certain embodiments, alkenyl groups are optionally substituted.
  • alkyl group that includes at least one carbon-carbon triple bond also is referred to by the term “alkynyl,” and in certain embodiments, alkynyl groups are optionally substituted.
  • an alkyl contains 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that an alkyl group can contain only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term “alkyl” also includes instances where no numerical range of carbon atoms is designated).
  • An alkyl can be designated as "Ci-C 4 alkyl" or by similar designations.
  • Ci-C 4 alkyl indicates an alkyl having one, two, three, or four carbon atoms, i.e., the alkyl is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, .sec-butyl and t-butyl.
  • Ci - C 4 includes Ci - C 2 , Ci - C 3 , C 2 - C 3 and C 2 - C 4 alkyl.
  • Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, hexenyl, ethynyl, propynyl, butynyl and hexynyl.
  • haloalkyl alone or in combination refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom.
  • the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.
  • Certain haloalkyls are saturated haloalkyls, which do not include any carbon-carbon double bonds or any carbon-carbon triple bonds.
  • Certain haloalkyls are haloalkenes, which include one or more carbon-carbon double bonds.
  • Certain haloalkyls are haloalkynes, which include one or more carbon-carbon triple bonds. In certain embodiments, haloalkyls are optionally substituted.
  • haloalkyl can include one or more of the same or different halogens.
  • haloalkyl includes each of the substituents CF 3 , CHF 2 and CH 2 F.
  • Pseudohalogen refers to compounds that behave substantially similar to halides/halogens. Such compounds can be used in the same manner and treated in the same manner as halides/halogens (X-, in which X is a halogen, such as Cl, F or Br). Pseudohalogens include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, trifluoromethyl and azide.
  • cycloalkyl refers to a saturated mono- or multicyclic ring system where each of the atoms forming a ring is a carbon atom. Cycloalkyls can be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. In one embodiment, the ring system includes 3 to 12 carbon atoms. In another embodiment, they ring system includes 3 to 6 carbon atoms.
  • cycloalkyl includes rings that contain one or more unsaturated bonds. As used herein, the terms “cycloalkenyl” and “cycloalkynyl” are unsaturated cycloalkyl ring system.
  • Cycloalkyls can be optionally substituted.
  • a cycloalkyl contains one or more unsaturated bonds.
  • Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1 ,4-cyclohexadiene, cycloheptane and cycloheptene.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic system that contains no ring heteroatoms. Where the systems are not monocyclic, the term aryl includes for each additional ring the saturated form (perhydro form) or the partially unsaturated form (for example the dihydro form or tetrahydro form) or the maximally unsaturated (nonaromatic) form. In some embodiments, the term aryl refers to bicyclic radicals in which the two rings are aromatic and bicyclic radicals in which only one ring is aromatic.
  • aryl examples include phenyl, naphthyl, anthracyl, indanyl, 1,2-dihydro-naphthyl, 1 ,4- dihydronaphthyl, indenyl, 1 ,4-naphthoquinonyl and 1 ,2,3,4-tetrahydronaphthyl.
  • Aryl rings can be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms.
  • aryl refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 1 1-, 12-, 13- or 14-membered, aromatic mono-, bi- or tricyclic system.
  • aryl refers to an aromatic C 3 -C 9 ring.
  • aryl refers to an aromatic C 4 -C 8 ring.
  • Aryl groups can be optionally substituted.
  • heteroaryl refers to an aromatic ring in which at least one atom forming the aromatic ring is a heteroatom.
  • Heteroaryl rings can be formed by three, four, five, six, seven, eight, nine and more than nine atoms.
  • Heteroaryl groups can be optionally substituted.
  • heteroaryl groups include, but are not limited to, aromatic C 3-8 heterocyclic groups containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring- forming carbon atoms.
  • heteroaryl is selected from among oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinal, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl.
  • a heteroaryl group is selected from among pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1 ,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl) pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5- tetrazinyl, indazolyl, indolyl, benzo thiophenyl, benzofuranyl, benzo
  • heteroaryl group includes more than one ring
  • each additional ring is the saturated form (perhydro form) or the partially unsaturated form (for example the dihydro form or tetrahydro form) or the maximally unsaturated (nonaromatic) form.
  • heteroaryl thus includes bicyclic radicals in which the two rings are aromatic and bicyclic radicals in which only one ring is aromatic.
  • heteroaryl examples include 3H-indolinyl, 2(lH)-quinolinonyl, 4-oxo-l,4-dihydroquinolinyl, 2H-l-oxoisoquinolyl, 1,2- dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1 ,2-dihydroiso- quinolinyl, 3,4-dihydro-isoquinolinyl, chromonyl, 3,4-dihydroiso-quinoxalinyl, 4- (3H)quinazolinonyl, 4H-chromenyl, 4-chromanonyl, oxindolyl, 1 ,2,3,4-tetrahydro- isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, lH-2,3-dihydroisoindolyl, 2,3- dihydrobenzo
  • heteroaryl groups are optionally substituted.
  • the one or more substituents are each independently selected from among halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci -6 -alkoxy, Ci -6 -alkyl, Ci -6 -haloalkyl, Ci -6 - hydroxyalkyl, Ci -6 -aminoalkyl, Ci ⁇ -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluorom ethyl.
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, fiirazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1 ,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, ,
  • the substituents are halo, hydroxy, cyano, O-Ci -6 -alkyl, Ci -6 -alkyl, hydroxy-Ci-6-alkyl and amino-Ci -6 -alkyl.
  • arylalkyl alone or in combination, refers to an alkyl substituted with an aryl that can be optionally substituted.
  • heteroarylalkyl alone or in combination, refers to an alkyl substituted with a heteroaryl that is optionally substituted.
  • the term "optionally substituted,” refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from among alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, C-amido, N- thiocarbamyl, N-amido, S-sulfonamido, N- sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono
  • Such protective derivatives are known to those of skill in the art and can be found in references such as Greene and Wuts ⁇ Protective Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, New York, NY, 1999), which is incorporated herein in its entirety.
  • the substituent groups can together form a ring.
  • non-aromatic heterocycle refers to a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom.
  • Non-aromatic heterocyclic rings can be formed by three, four, five, six, seven, eight, nine, or more than nine atoms.
  • Non-aromatic heterocycles can be optionally substituted.
  • non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1 ,3-oxathiane, 1 ,4-oxathiine, 1 ,4-oxathiane, tetrahydro-l ,4-thiazine, 2H- 1 ,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro- 1 ,3,5- triazine,
  • enantiomer refers to one of a pair of molecular entities that are mirror images of each other and non-superimposable.
  • Enantiomeric excess (ee) can be calculated for a mixture of (R) and (S)-enantiomers.
  • the ee can be defined as the absolute value of the mole fractions of F (R) minus the mole fraction of F ( s>.
  • the percent ee then is the absolute value of the mole fractions of F( R ) minus the mole fraction of F $) multiplied by 100.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • substantially pure object species e.g., compound
  • is the predominant species present i.e., on a molar basis it is more abundant than any other individual species in the composition.
  • a substantially purified fraction is a composition wherein the object species includes at least about 50 percent (on a molar basis) of all species present.
  • a substantially pure composition will include more than about or 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • a substantially pure composition will include more than about or 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art.
  • a substantially chemically pure compound can, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • all tautomeric forms also are intended to be included.
  • the compounds described herein can be administered alone or in combination with one or more than one other active ingredient or drug or agent.
  • co-administer refers to administering more than one pharmaceutical agent to a subject.
  • co-administered pharmaceutical agents are administered together in a single dosage unit.
  • co-administered pharmaceutical agents are administered separately.
  • co-administered pharmaceutical agents are administered at the same time.
  • co-administered pharmaceutical agents are administered at different times.
  • PO refers to Per Os, meaning by mouth or orally.
  • subject is an animal, typically a mammal, including human.
  • patient includes human and animal subjects.
  • tissue-selective refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue.
  • the biological activities in the different tissues can be the same or they can be different.
  • the biological activities in the different tissues can be mediated by the same type of target receptor.
  • a tissue-selective compound can modulate an androgen receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, an androgen receptor mediated biological activity in another tissue type.
  • the term "monitoring” refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound provided herein. Examples of effects that can be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, androgen receptor activity, or the interaction between an androgen receptor and a natural binding partner.
  • cell phenotype refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis, or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art.
  • a metabolic nutrient e.g., glucose uptake
  • contacting refers to bringing two or more materials into close enough proximity whereby they can interact.
  • contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like.
  • contacting can be performed in the presence of additional materials.
  • contacting can be performed in the presence of cells.
  • one or more of the materials that are being contacted can be inside a cell. Cells can be alive or can be dead. Cells can or can not be intact.
  • arthritic condition or “arthritis” refers to a disease whose underlying etiology is inflammation of a joint, usually accompanied by pain, such as osteoarthritis and rheumatoid arthritis (Taber's Cyclopedic Medical Dictionary; 14 th edition, 1983).
  • the compounds disclosed herein are useful, alone or in combination, to treat or prevent arthritic conditions.
  • Exemplary arthritic conditions include Behcet's disease; bursitis and tendinitis; CPPD deposition disease; carpal tunnel syndrome; Ehlers-Danlos syndrome; fibromyalgia; gout; infectious arthritis; inflammatory bowel disease; juvenile arthritis; lupus erythematosus; Lyme disease; Marfan syndrome; myositis; osteoarthritis; osteogenesis imperfecta; osteonecrosis; polyarteritis; polymyalgia rheumatica; psoriatic arthritis; Raynaud's phenomenon; reflex sympathetic dystrophy syndrome; Reiter's syndrome; rheumatoid arthritis; scleroderma; and Sjogren's syndrome.
  • NSAIDs refer to non-steroidal anti-inflammatory drugs.
  • NSAIDs include, but are not limited to, aspirin, diclofenac/misoprostol, diclofenac potassium, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefanamic acid, meloxicam, nabumetone, naproxen and naproxen sodium, oxaprozin, piroxicam, sodium sulindac and tolmetin.
  • COX-2 inhibitors refers to drugs that inhibit only the inducible form of the Cyclooxygenase (COX) enzyme (EC 1.14.99.1), which is referred to as COX-2.
  • COX Cyclooxygenase
  • COX-2 inhibitors include, but are not limited to, celecoxib, rofecoxib and valdecoxib.
  • DMARDs Disease-Modifying Anti-Rheumatic Drugs
  • RA rheumatoid arthritis
  • psoriatic arthritis rheumatoid arthritis
  • DMARDs have been shown to be effective in the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis and, for some subjects, these drugs can stop progression of the disease.
  • Exemplary DMARDs include, but are not limited to, adalimumab, leflunomide, auranofin, sodium aurothiomalate, chloroquine, etanercept, infliximab, sulfasalazine, mycophenolate, myochrysine, cyclosporine, cyclophosphamide, azathioprine, chlorambucil, methotrexate, minocycline, penicillamine and hydroxychloroquine.
  • photodynamic therapy dyes refers to any of the conjugated or unconjugated dyes or pigments used in photodynamic therapy.
  • the photodynamic therapy dyes include porphyrins, chlorines, purpurins, benzoporphyrins and other dyes and pigments that absorb light of a particular wavelength, thereby initiating tumor necrosis presumably through formation of singlet oxygen or other destructive chemical species.
  • Photodynamic therapy for the treatment of cancer is well known in the art (e.g., see U.S. Pat. Nos. 7,018,395, 7,01 1 ,812, 6,806,284, 6,723,750, 6,710,066 and 6,630,128).
  • toxins and cytotoxic drugs refers to chemical molecules that are known to affect the growth and action of some cells, and in some instances leads to the death of the cell when the cells are exposed to the chemical molecules.
  • toxins and cytotoxic agents include, but are not limited to, adrenocortical suppressants, such as mitotane; alkyl sulfonates, such as busulfan; ethylenimine derivatives, such as thiotepa; nitrosoureas, such as carmustine, lomustine, semustine and streptozocin; folic acid analogs, such as methotrexate; methyl hydrazine derivatives, such as procarbazine; nitrogen mustards, such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard and chlorambucil; purine analogs, such as mercaptopurine and thioguanine; pyrimidine analogs, such as fluorouracil, cytarabine and azaribine; substituted urea compounds, such as hydroxyurea; taxol; triazenes, such as dacarbazine; and vinca
  • an "antiproliferative agent” refers to any agent that reduces the rate or level of cellular proliferation.
  • the agent can reduce proliferation by inducing apoptosis, modulating cellular microtubule structure (e.g., promoting microtubule polymerization), inhibiting tyrosine kinase mediated signaling, antagonizing cell surface receptor binding (e.g., EGFR and VEGFR inhibitors), modulating glucocorticoid receptor functioning, down-regulating angiogenesis (e.g., inhibiting VEGF functioning) or inducing cell death.
  • an "anti-tumor agent” refers to any agent that limits the growth of or destroys a tumor, and includes the following classes of compounds: angiogenesis inhibitors, DNA intercalators / cross-linkers, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulators and microtubule inhibitors.
  • angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors FIt-I (VEGFRl) and FIk-I /KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ , interleukin- 12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal antiinflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclo- oxygenase-2 inhibitors like celecoxib and rofecoxib, steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, steroidal anti-
  • VEGF vascular endothelial growth factor
  • Other therapeutic agents that modulate or inhibit angiogenesis include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38: 679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3- hydroxy-3 -methyl glutaryl-Co A reductase.
  • exemplary HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239), pravastatin (see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (see U.S.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds that have HMG-CoA reductase inhibitory activity.
  • a "synthetic estrogen” refers to non-naturally occurring compounds that exhibit at least some of the properties of 17/3-estradiol when administered to a subject.
  • exemplary synthetic estrogens include ethinyl estradiol, diethylstilbestrol (DES), chlorotrianisene, dienestrol, ethinyl estradiol and ethinyl estradiol 3-cyclopentyl ether.
  • estradien receptor agonist refers to a compound that acts at an estrogen receptor and has at least some of the same biological effects as 17/3-estradiol.
  • estradien receptor antagonists Compounds that act at an estrogen receptor to block the effects of 17/3- estradiol are called “estrogen receptor antagonists.”
  • SERMs selective estrogen receptor modulators
  • Exemplary SERMs include apeldoxifene, clomifene, fulvestrant, lasofoxifene, raloxifene, tamoxifen and toremifene.
  • osteoporosis refers to the condition characterized by reduced bone mass and disruption of bone architecture, resulting in increased bone fragility and increased fracture risk, and decreased calcification or density of bone. Osteoporosis is a thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein. In osteoporotic patients, bone strength is abnormal, with a resulting increase in the risk of fracture.
  • the fracture can be in the form of cracking (as in a hip fracture) or collapsing (as in a compression fracture of the spine).
  • the spine, hips, and wrists are common areas of osteoporosis-induced bone fractures, although fractures also can occur in other skeletal areas. Unchecked osteoporosis can lead to changes in posture, physical abnormality and decreased mobility. Osteoporosis can be identified by bone mineral density measurements.
  • osteopenia refers to decreased calcification or density of bone.
  • a “cathepsin inhibitor” refers to an inhibitor of cysteine protease. Cysteine proteases, such as cathepsins, are linked to a number of disease conditions, including arthritis, bone remodeling, inflammation and tumor metastasis. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and thus are useful in the treatment of bone resorption diseases, such as osteoporosis. Examples of cathepsin inhibitors are described in
  • a "proton pump inhibitor” refers to osteoclast vacuolar ATP ase inhibitors.
  • the proton ATP ase found on the apical membrane of the osteoclast has been reported to play a significant role in the bone resorption process and is a target for the design of inhibitors of bone resorption, thereby useful for the treatment and prevention of osteoporosis and related metabolic diseases (e.g., see Niikura, Drug News Perspect. 19(3): 139-44 (2006), Visentin et al, J Clin Invest 106(2): 309-318 (2000) and Niikura et al., Br J of Pharmacology 142: 558-566 (2004)).
  • Exemplary inhibitors include bafilomycin Al, SB242784, FR167356, FR177995, FR202126, FR133605 and NiK-12192 [4-(5,6-dichloro-lH-indol-2-yl)-3- ethoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide] (Petrangolini et al., J Pharmacol Exp Ther 318 (3): 939-946 (2006).
  • PPAR ⁇ activators refers to activators of the peroxisome proliferator-activated receptor gamma (PPAR ⁇ ), which are known in the art to inhibit osteoclast-like cell formation and bone resorption (e.g., see Okazaki et al., Endocrinology 140: 5060-5065 (1999)).
  • PPAR ⁇ activators include the glitazones, such as ciglitazone, darglitazone, englitazone, troglitazone, pioglitazone, rosiglitazone, the thiazolidinediones (see, e.g.
  • muscle wasting refers to atrophy or loss of muscle tissue, which can result from disease or disuse (lack of exercise). As used herein, muscle wasting also includes loss of muscle tone and neurogenic atrophy. Muscle wasting is characterized by a weakening, shrinking, and loss of muscle tissue, often caused by degradation of the contractile myofibrillar proteins actin and myosin (e.g., see
  • chronic muscle wasting refers to chronic ⁇ i.e., persisting over a long period of time) progressive loss of muscle mass and/or to the chronic progressive weakening and degeneration of muscle.
  • Cachexia refers to weakness and a loss of weight caused by a disease or as a side effect of illness. Cardiac cachexia, which includes muscle protein wasting of both the cardiac and skeletal muscle, is a characteristic of congestive heart failure. Cancer cachexia is a syndrome that occurs in patients with solid tumors and hematological malignancies and is manifested by weight loss with massive depletion of both adipose tissue and lean muscle mass. Cachexia also occurs in acquired immunodeficiency syndrome (AIDS). Human immunodeficiency virus (H ⁇ V)-associated myopathy and/or muscle weakness/wasting is a relatively common clinical manifestation of AIDS. Individuals with HIV-associated myopathy or muscle weakness or wasting typically experience significant weight loss, generalized or proximal muscle weakness, tenderness, and muscle atrophy.
  • H ⁇ V Human immunodeficiency virus
  • sarcopenia refers to a debilitating disease that afflicts the elderly and chronically ill patients and is characterized by loss of muscle mass and function.
  • the term “obesity” refers to the state of being well above one's normal weight. Traditionally, a person is considered to be obese if they are more than 20 percent over their ideal weight. Obesity has been defined by the National Institute of Health (NIH) as a Body to Mass Index (BMI) of 30 or above. Overweight due to obesity is a significant contributor to health problems.
  • NASH National Institute of Health
  • BMI Body to Mass Index
  • obesity includes any one of the above-listed obesity-related conditions and diseases.
  • cancer or "neoplastic disease” refers to a broad group of malignant neoplasms, growth or tumor caused by abnormal and uncontrolled cell division, and includes carcinomas and sarcomas (Taber 's Cyclopedic Medical Dictionary, 14 th edition, 1983). In additional to their uncontrolled growth, cancer cells invade and destroy adjacent tissues and often metastasize to new sites within the body.
  • treating cancer refers to administration of a treatment to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, as well as an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • lipid profile refers to total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), very low density lipoprotein (VLDL), and triglycerides in a subject.
  • LDL, HDL and VLDL are the three types of lipoproteins found in the blood, and they usually represent the types of cholesterol found in the blood (cholesterol combined with a protein and triglyceride).
  • anemia refers to the condition of having less than the normal number of red blood cells or less than the normal quantity of hemoglobin in the blood. Because of the decreased number of red blood cells or reduced quantity of hemoglobin, the oxygen-carrying capacity of the blood is decreased. A subject with anemia may feel tired and fatigue easily, appear pale, develop palpitations and become usually short of breath. There are many forms of anemia, including aplastic anemia, Fanconi anemia, hereditary spherocytosis, iron deficiency anemia, osteopetrosis, pernicious anemia, sickle cell disease, thalassemia, myelodysplasia syndrome, and a variety of bone marrow diseases.
  • depression refers to an illness that involves the body, mood and thoughts, that affects the way a person eats and/or sleeps and the way one feels about oneself and thinks about things.
  • the signs and symptoms of depression include loss of interest in activities, loss of appetite or overeating, loss of emotional expression, an empty mood, feelings of hopelessness, pessimism, guilt or helplessness, social withdrawal, fatigue, sleep disturbances, trouble concentrating, remembering, or making decisions, restlessness, irritability, headaches, digestive disorders or chronic pain.
  • sexual dysfunction refers to impairment of the emotional or physical responses associated with sexual activity, including sexual desire disorders, sexual arousal disorders, orgasm disorders, and sexual pain disorders, which can prevent an individual from engaging in sexual activity or result in inadequate sexual functioning.
  • sexual dysfunction includes lack of sexual desire, anxiety about sexual performance, difficulty in becoming aroused, inability to achieve orgasm (anorgasmia), premature ejaculation, erectile dysfunction, impotence, frigidity, dyspareunia, vaginismus and dyspareunia (e.g., see American Society for Reproductive Medicine, "Sexual Dysfunction - Patient's Fact Sheet” (1998)).
  • male sexual dysfunction includes impotence, loss of libido, orgasm dysfunction (e.g., premature ejaculation or retrograde ejaculation) and erectile dysfunction.
  • erectile dysfunction refers to a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm.
  • An increase in erectile dysfunction and sexual dysfunction can have numerous underlying causes, including but not limited to (1) aging, (b) an underlying physical dysfunction, such as trauma, surgery, and peripheral vascular disease, and (3) side-effects resulting from drug treatment, depression, and other CNS disorders.
  • female sexual dysfunction includes dysfunction in desire, sexual arousal, sexual receptivity, and orgasm related to disturbances in the clitoris, vagina, periurethral glans, and other trigger points of sexual function.
  • anatomic and functional modification of such trigger points may diminish the orgasmic potential in breast cancer and gynecologic cancer patients.
  • Treatment of female sexual dysfunction with an SARM compound provided herein can result in improved blood flow, improved lubrication, improved sensation, facilitation of reaching orgasm, reduction in the refractory period between orgasms, and improvements in arousal and desire.
  • libido refers to sexual desire.
  • hypogonadism refers to a condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development.
  • cognition refers to the process of knowing, specifically the process of being aware, knowing, thinking, learning and judging.
  • miod refers to a temper or state of the mind.
  • alteration or “alterations” refers to any change for the positive or negative, in cognition and/or mood.
  • hair loss refers to alopecia, or baldness, such as in the common type of male-pattern baldness. Hair loss affects both males and females.
  • “frailty” refers to an adverse, primarily gerontologic, health condition, characterized by low functional reserve, accelerated osteoporosis, easy tiring, decreased muscle strength, high susceptibility to disease and decreased libido (e.g., see Bandeen-Roche et al., The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61 : 262-266 (2006)).
  • bioavailability refers to the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action or reaches systemic circulation.
  • the “absolute bioavailability” of a given pharmaceutical form is compared to that following intravenous administration, which is by definition 100%. Administration by a route other than intravenous administration generally is less than 100%, due to slow or incomplete absorption, or metabolic destruction.
  • “Good bioavailability” generally is >50% and “poor bioavailability” generally is ⁇ 20%.
  • androgenic activity refers to androgen receptor (AR) agonist activity in androgenic target tissues, such as prostate and seminal vesicles. Androgenic activity is typically demonstrated by increases in the weights of the prostate and seminal vesicles, which are accepted in the art as indicators of androgenic activity (e.g., see Lemus et al., J Steroid Biochem MoI Biol 60(1-2): 121- 129 (1997)).
  • androgenic effect or “androgenic effects” refers to producing or enhancing male traits, and includes producing side effects associated with administration of steroidal androgens such as testosterone. These adverse androgenic effects include manifestations such as prostate enlargement, acne, repression of high density lipoprotein cholesterol (HDL), hirsutism, virilization and masculinization.
  • HDL high density lipoprotein cholesterol
  • anabolic activity refers to increasing the mass and/or strength of a tissue, such as a connective tissue. Increases in the weight of the levator ani muscle are indicative of anabolic activity, and are accepted in the art as a reliable index of anabolic activity (e.g., see Antonio et al., J Appl Physiol 87: 2016-2019 (1999)). Anabolic activity in bone and muscle decreases bone fracture rates in a subject. Anabolic activity of the compounds provided herein on muscle can be tested by assessing expression of MHC subtypes in skeletal muscle ⁇ e.g., see Wright et al., J Appl Physiol. 83(4): 1389-96 (1997)).
  • Bone formation rate another indication of anabolic activity, can be assessed by osteocalcin level measurement.
  • Plasma osteocalcin levels can be determined using any method known in the art (e.g., see Koyama et al, J Immunol Methods 139(1): 17-23 (1991)).
  • a rat osteocalcin EIA kit is commercially available from Biomedical Technologies Inc. (Stoughton, MA).
  • connective tissue refers to tissue generally of mesodermal origin that is characterized by a highly vascular matrix and which forms the supporting and connecting structures of the body.
  • Connective tissue includes collagenous, elastic, and reticular fibers, muscle, adipose tissue, cartilage, and bone.
  • Exemplary connective tissue includes adipose tissue, areolar tissue, blood, bone (including cancellous bone, compact bone, cortical bone, spongy bone and trabecular bone), bone marrow, cartilage, collagen, cutis, elastic tissue, endoneurium, fascia, ligament, mesenchymal connective tissue, mucous connective tissue, muscle, osseous tissue, perineurium, perimysium, submucosa and tendon.
  • bone mineral density or “BMD” refers to the density of minerals (such as calcium) in bone. BMD is determined using a special X-ray, computed tomography (CT) scan, or ultrasound. This information is used to estimate the strength of bones. Increasing mineral content of bone increases the density of the bone and its strength. The denser the bone, the less likely it is to break.
  • unit dosage forms refers to physically discrete units suitable for human and animal subjects. Each unit dosage includes a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with, when required, a pharmaceutical carrier, vehicle or diluent.
  • unit dosage forms examples include tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, ampoules and syringes, and oral solutions or suspensions, and oil-water emulsions.
  • Unit dosage forms can be individually packaged as is known in the art, such as in blister packs.
  • Unit dosage forms can be administered in fractions or multiples thereof.
  • “multiple dosage forms” refers to a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dosage form.
  • Examples of multiple dosage forms include vials, bottles of tablets or capsules or bottles of pints or gallons of liquid containing the active compound.
  • a multiple dosage form is a multiple of unit dosages which are not segregated in packaging.
  • non-specific binding refers to that binding remaining in the presence of an excess of unlabeled specific ligand (i.e., in the case of androgen receptor, 1000 nM of unlabeled dihydrotestosterone).
  • potency refers to the dose of drug required to produce a specific effect of given intensity as compared to a standard reference.
  • AUC refers to the area under the plasma concentration-time curve and can be used as a metric for extent of exposure of a pharmaceutical.
  • exposure refers to AUC and the term “total exposure” refers to AUCo -00 .
  • AUCo -00 or "AUC 0- j nf” refers to the area under the concentration-time curve from time zero to infinity (extrapolated).
  • AUC 0-00 can be calculated as AUC 0-1 + (Q/ Ka) where Q is the calculation at time t.
  • the term "AUC 0 . t " refers to the area under the concentration- time curve from time zero to time of last non-zero (last measurable) concentration.
  • the linear trapezoidal rule can be used to calculate AUC 0-t .
  • the term “AUC x " refers to the area under the concentration- time curve from time zero to x hours post dose.
  • AUC 6 refers to the area under the concentration-time curve from time zero to 6 hours post-administration
  • AUC 24 refers to the area under the concentration-time curve from time zero to 24 hours post-administration.
  • C MAX refers to the maximum (peak) observed plasma concentration.
  • C MIN refers to the minimum observed plasma concentration, which also can be referred to as the trough concentration.
  • T MAX refers to the time to reach the maximum (peak) observed plasma concentration C MAX -
  • the term "apparent half-life" or “V” refers to the apparent time required for half the quantity of a drug or other substance administered to an organism to be metabolized or eliminated.
  • R 1 is halogen, pseudohalogen, optionally substituted lower alkyl, optionally substituted haloalkyl or NO 2 ;
  • R 2 is hydrogen, halogen, pseudohalogen, optionally substituted lower alkyl or optionally substituted lower haloalkyl;
  • R 3 is hydrogen, halogen, pseudohalogen, optionally substituted lower alkyl or optionally substituted lower haloalkyl;
  • R 4 is halogen or lower haloalkyl; and
  • R 5 is lower alkyl or lower haloalkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof.
  • R 1 is lower haloalkyl or halogen;
  • R 2 is hydrogen or lower alkyl;
  • R 3 is hydrogen or lower alkyl;
  • R 4 is CF 3 or halogen; and
  • R 5 is Ci to C 4 alkyl or Ci to C 4 haloalkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof.
  • R 1 is CF 3 , F, or Cl;
  • R 2 is H or methyl;
  • R 3 is H or methyl;
  • R 4 is Cl or CF 3 ; and
  • R 5 is methyl, ethyl or CF 3 ; and pharmaceutically acceptable salts, esters and prodrugs thereof.
  • substituents can be selected from among a subset of the listed alternatives.
  • R 1 is CF 3 . In certain embodiments, R 1 is F or Cl. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl.
  • R 2 is H. In certain embodiments, R 2 is methyl. In certain embodiments, R 3 is H. In certain embodiments, R 3 is methyl. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is CF 3 .
  • R 5 is methyl or ethyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is ethyl. In certain embodiments, R 5 is CF 3 .
  • the compounds provided herein include: JR,7?-4-(2-(l-Hydroxyl-2,2,2-trifluoroethyl)py ⁇ Olidinyl)-2- trifluoromethylbenzonitrile;
  • the target tissue is connective tissue.
  • the target tissue is muscle.
  • the target tissue is bone.
  • the compounds provided herein have anabolic activity and promote tissue formation and/or growth.
  • the compounds provided herein can demonstrate full agonist activity in connective tissue without adverse androgenic effects.
  • the compounds provided herein can demonstrate full agonist activity in muscle, resulting in increased or improved muscle mass and muscle strength without adverse androgenic effects.
  • the compounds provided herein can demonstrate full agonist activity in bone, resulting in increased or improved bone density and strength without adverse androgenic effects.
  • the SARM compounds provided herein have utility in treating conditions that are remediated by anabolic activity (e.g., reversing connective tissue loss).
  • the compounds provided herein also are androgen receptor selective binding compounds, in that they bind to any portion of an androgen receptor with a greater affinity than they bind to a non-androgen receptor, such as, but not limited to, a progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), retinoic acid receptor (RAR), rexinoid receptor (RXR), or peroxisome proliferator-activated receptor (PPAR).
  • PR progesterone receptor
  • ER estrogen receptor
  • GR glucocorticoid receptor
  • MR mineralocorticoid receptor
  • RAR retinoic acid receptor
  • RXR rexinoid receptor
  • PPAR peroxisome proliferator-activated receptor
  • Compound 102 compound 4-(2(i?)-(l(5 > )-hydroxyl-2,2,2-trifluoroethyl)- pyrrolidinyl)-2-trifluoromethylbenzonitrile (Compound 102) is a potent AR agonist with tissue selectivity and is highly selective for the AR receptor. It has been shown to be orally bioavailable in multiple animal species, including monkeys, indicating good bioavailability in humans. Based on its plasma half-life it can be formulated for administration as a once or twice a day drug. It has shown good tolerance and safety in a multiple dose toxicology study. It is negative for genotoxicity in in vitro assays. Certain compounds provided herein can exist as stereoisomers, including optical isomers.
  • the present disclosure is intended to include all stereoisomers and the racemic mixtures of such stereoisomers as well as the individual enantiomers that can be separated according to any of a number of conventional methods that are known in the art. These methods include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
  • Scheme I describes the preparation of compounds of Formula I (shown as Structure 3 in Scheme I).
  • 2-Chloro-4-fluoro-3-methylbenzonitrile can be prepared using methods known in the art. For example, 2-Chloro-4-fluorobenzonitrile (1 g) and TMEDA (1.13 mL) in THF (10 mL) were cooled to -78°C, under nitrogen. -Sec-butyllithium (1.3M in cyclo- hexane, 8.54 mL) was added over 20 min, keeping the temperature below -70°C. The mixture was then stirred at -78°C for 2.5 h. Methyl iodide (0.5 mL) was added and the mixture allowed to warm to 15°C, over 35 min.
  • 2-Chloro-4-fluoro-3-methylbenzonitrile also can be synthesized by adding 3- bromo-2-chloro-6-fluorotoluene (173 mg, 0.78 mmol), zinc cyanide (91 mg, 0.78 mmol), tetrakis-(triphenylphosphine)palladium(0) (27 mg, 23 Tmol) and DMF (1 mL) to a vial, and after sealing the vial, irradiating the mixture for 150 sec at 200°C in a microwave oven. Diethyl ether (30 ml) is then added and the reaction mixture washed with magnesium sulphate (4% solution, 3 x 20 mL) followed by brine (20 mL).
  • Scheme II describes the preparation of compounds of Formula II where R 4 is CF 3 (shown as Structure 15 in Scheme II).
  • R 4 is CF 3
  • Scheme II describes the preparation of compounds of Formula II where R 4 is CF 3 (shown as Structure 15 in Scheme II).
  • Scheme II describes the preparation of compounds of Formula II where R 4 is CF 3 (shown as Structure 15 in Scheme II).
  • Reduction of the halide group can be achieved by chemical reduction, with, for example, a metal catalyst, for example, 10% Pd-C, in a hydrogen atmosphere, to afford a compound of Structure 8.
  • Conversion of the aniline ring to a phenol ring can be effected by treatment of Structure 8 with a diazotizing agent, for example, sodium nitrite in sulfuric acid, to afford a compound of Structure 9.
  • Bromination of the phenol ring with a brominating reagent, for example, N- bromosuccinimide, in the presence of a base, for example, diisopropylamine affords a compound of Structure 10 (see, e.g., Fujisaki et al., Bull. Chem. Soc. Jpn. 66: 1576- 1579 (1993), the disclosure of which is herein incorporated by reference.
  • Selective protection of the phenolic oxygen can be achieved by treatment of
  • Structure 10 with an alkyl halide, for example, benzyl bromide, in the presence of a base, for example, cesium fluoride, to afford the corresponding ether. Protection of the pyridone ring, with, for example isopropyl iodide, mediated by a base, for example, cesium fluoride, affords the corresponding imino ether (Structure 11). Selective hydrolysis of the phenolic ether can be accomplished by acidic hydrolysis, with, for example, a 1 :1 mixture of methanesulfonic acid and acetic acid, to afford a compound of Structure 12.
  • a base for example, cesium fluoride
  • the compound of Structure 14 is prepared by alkylation of the phenolic oxygen of Structure 12 by treatment with a protected amino alcohol 13.
  • Mitsunobu conditions for example, triphenylphosphine and diisopropyl azodicarboxylate
  • a base for example, N- methylmorpholine
  • Closure of the amine to the aromatic halide can be achieved by treatment with a transition metal, for example Pd 2 (dba) 3 in the presence of a ligand, for example, BINAP, and a base, for example, sodium t-butoxide, to afford a compound of Structure 14 (see, Wagaw et al., J. Am. Chem. Soc. 119: 8451- 8458 (1997)).
  • a transition metal for example Pd 2 (dba) 3
  • a ligand for example, BINAP
  • a base for example, sodium t-butoxide
  • Scheme IV describes the preparation of compounds of Formula III (shown as Structure 20 is Scheme IV).
  • Androgen therapy has been used to treat a variety of male disorders such as reproductive disorders and primary or secondary male hypogonadism.
  • a number of natural or synthetic AR agonists have been investigated for the treatment of musculoskeletal disorders, such as bone disease, hematopoietic disorders, neuromuscular disease, rheumatological disease, wasting disease, and for hormone replacement therapy (HRT), such as female androgen deficiency.
  • AR antagonists such as fiutamide and bicalutamide, are used to treat prostate cancer. Progress of androgen therapy has been limited by the inability to separate desirable androgenic activities from undesirable or dose-limiting side effects.
  • SARMs selective androgen receptor modulators
  • the compound LG 120907 a non-steroidal AR antagonist
  • rats have reduced antagonist effects on the hypothalamic axis and on libido (reproductive rate) as compared to other clinically used AR antagonists, such as Casodex, and has been characterized as a selective androgen receptor modulator for the treatment of prostate cancer (e.g., see Gao et al, Pharmaceutical Research 23(8): 1641-1658 (2006)).
  • Other SARMs and uses thereof have been identified in the art (e.g., see U.S. Pat. Appl. No. US2007254875 and U.S. Pat. Nos.
  • This class of ligands demonstrates better pharmacokinetic and specificity profiles than other steroidal therapies.
  • non-steroidal SARMs display therapeutic benefit but do not display the androgenic effects associated with other steroidal therapies.
  • adverse androgenic effects include manifestations such as prostate enlargement, acne, repression of high density lipoprotein cholesterol (HDL), hirsutism, virilization and masculinization.
  • HDL high density lipoprotein cholesterol
  • the compounds provided herein are SARMs.
  • Compounds provided herein demonstrate the ability to exhibit their activity on the androgen receptor in a tissue- selective manner. This tissue selectivity allows the compounds provided herein to function as an agonist in some tissues, while having no effect or even an antagonist effect in other tissues. The molecular basis for this tissue selective activity is not completely understood. Without being limited to any particular explanation, particular ligands put nuclear receptors in different conformational states. These states dictate the ability of co-activators, co-repressors, and other proteins to be recruited by the nuclear receptor. The combination of the nuclear receptor different co-activators, co-repressors, and other proteins are the gene transcription factors that are thought to modulate tissue-selective effects.
  • SARMs exhibit agonistic anabolic properties and antagonistic androgenic properties.
  • Compounds provided herein have anabolic building activity, such as in muscle and bone, without unwanted androgenic side effects on most other tissues, such as prostate and skin sebaceous glands.
  • Compounds provided herein are tissue-selective modulators of the androgen receptor.
  • the compounds provided herein can be used to activate the function of the androgen receptor in a subject, and in particular to activate the function of the androgen receptor in bone and/or muscle tissue and block or inhibit (antagonize) the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual.
  • compounds provided herein exhibit antagonist activity in hormone-dependent tumors while exhibiting no activity, or in some embodiments agonist activity, against other non-tumor tissues containing the androgen receptor.
  • these SARMs can be used to treat a number of androgen receptor- mediated conditions, including treatment of hormone-dependent tumors containing AR, such as prostate cancer, in patients by inhibiting the growth of the tumor while mitigating side effects such as muscle wasting, cachexia, sexual dysfunction such as loss of libido, osteoporosis and gynecomastia.
  • the compounds provided herein typically display micromolar or submicro- molar binding affinity for the androgen receptor.
  • the compounds provided herein demonstrate AR agonist or antagonist activity, as evidenced by their activity in standard AR agonist and antagonist assays, such as the co-transfection assay described herein.
  • compounds provided herein demonstrate a potency (EC 50 ) of 1 ⁇ M or less in the co-transfection assay described herein.
  • compounds provided herein demonstrate a potency (EC 5 o) of 100 nM or less.
  • compounds provided herein demonstrate a potency (EC 50 ) of 50 nM or less.
  • compounds provided herein demonstrate a potency (EC 50 ) of 10 nM or less.
  • Compounds provided herein also demonstrate an efficacy of 50% or greater in a standard AR agonist assay.
  • the compounds provided herein are therefore useful in treating mammals suffering from disorders related to androgen receptor function.
  • Therapeutically effective amounts of one or more of the compounds provided herein, or any of the pharmaceutically acceptable salts thereof, are administered to the subject, to treat disorders related to androgen receptor function, such as, androgen deficiency, disorders that can be ameliorated by androgen replacement, or that can be improved by androgen replacement, or to treat disorders that are responsive to treatment with an anti- androgen.
  • Treatment is effected by administration of a therapeutically effective amount of one or more than one of the compounds provided herein to a subject in need of such treatment.
  • these compounds are useful as ingredients in pharmaceutical compositions alone or in combination with other active agents.
  • compounds and/or compositions provided herein are used for the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated with androgen receptor activity.
  • the diseases and disorders that are treated include those caused by androgen deficiency and/or those that can be ameliorated by androgen administration, as well as those whose etiology involves hyperactivity of androgen receptor and/or those that can be ameliorated by anti-androgen administration.
  • disorders, diseases or conditions that are caused by androgen deficiency or hypoactivity or subsensitivity of androgen receptor, or that can be ameliorated by androgen replacement or are responsive to treatment with an AR agonist include, but are not limited to, aging skin; Alzheimer's disease; anemias, such as for example, aplastic anemia; anorexia; arthritis, including inflammatory arthritis, rheumatoid arthritis, osteoarthritis and gout; arteriosclerosis; atherosclerosis; bone disease, including metastatic bone disease; bone damage or fracture, such as by accelerating bone fracture repair and/or stimulation of osteoblasts and/or stimulation of bone remodeling and/or stimulation of cartilage growth; distraction osteogenesis; reduced bone mass, density or growth; bone weakening, such as induced by glucocorticoid administration; musculoskeletal impairment (e.g., in the elderly); cachexia; cancer, including breast cancer and osteosarcoma; cardiac dysfunction (e.g., associated with valvular disease, myocardial infar
  • the compounds provided herein that demonstrate AR agonist activity also can be used to stimulate pulsatile growth hormone release; to improve bone strength, muscle strength and tone; to reduce subcutaneous fat in a subject; to enhance bone and muscle performance/strength; to increase athletic performance; to attenuate or reverse protein catabolic responses following trauma (e.g., reversal of the catabolic state associated with surgery, congestive heart failure, cardiac myopathy, burns, cancer, COPD); to improve sleep quality and/or correct the relative hyposomatotropism of senescence due to high increase in REM sleep and a decrease in REM latency; to treat age related decreased testosterone levels in men; to modifying lipid profile; and for hormone replacement therapy, such as female androgen deficiency and male androgen decline.
  • trauma e.g., reversal of the catabolic state associated with surgery, congestive heart failure, cardiac myopathy, burns, cancer, COPD
  • SARMs can act as antagonists in specific tissues, and thus also are useful in treating conditions where elevated androgen concentration or activity causes symptoms.
  • the compounds provided herein that demonstrate AR antagonism can be used to treat conditions whose etiology involves hyperactivity of androgen receptor or that are responsive to treatment with an AR antagonist.
  • Such conditions include, but are not limited to, acanthosis nigricans, acne, adrenal hyperandrogenism, androgenetic alopecia (male-pattern baldness), adenomas and neoplasias of the prostate (e.g., advanced metastatic prostate cancer), benign prostate hyperplasia, cancer (e.g., cancer of the breast, bladder, endometrium, lung (non-small cell lung cancer), pancreas, prostate, including androgen dependent prostate cancer, and skin ); bulimia nervosa; chronic fatigue syndrome (CFS); chronic myalgia; acute fatigue syndrome; contraception; counteracting preeclampsia, eclampsia of pregnancy and preterm labor; delayed wound healing; erythrocytosis; gestational diabetes; hirsutism; hyper-insulinemia including nesidioblastosis; hyperandrogenism; hypercortisolism; Cushing's syndrome; hyperpilosity; infertility
  • the compounds provided herein have an agonistic activity on muscle and bone tissue, and have a neutral or antagonistic effect on prostate tissue. In some embodiments, such compounds are used to treat or prevent a condition selected from among muscle wasting, cachexia, frailty, sarcopenia, osteopenia, osteoporosis, hypogonadism and sexual dysfunction.
  • the compounds provided herein have no effect on muscle and/or bone, and have neutral or antagonistic effect on prostate. In some embodiments, such compounds are used to treat or prevent a condition selected from among benign prostatic hyperplasia (BPH), prostate cancer and sexual dysfunction.
  • BPH benign prostatic hyperplasia
  • prostate cancer prostate cancer
  • Muscle wasting is associated with chronic, neurological, genetic or infectious pathologies, diseases, illnesses or conditions.
  • the pathology, illness, disease or condition is chronic.
  • the pathology, illness, disease or condition is genetic.
  • the pathology, illness, disease or condition is neurological.
  • the pathology, illness, disease or condition is infectious.
  • the pathologies, diseases, conditions or disorders for which the compounds and compositions provided herein are administered are those that directly or indirectly produce a loss of muscle mass, or that result in a muscle wasting disorder.
  • Muscle wasting infectious pathologies, diseases, illnesses or conditions include acquired immunodeficiency syndrome (AIDS); burns; cachexias, such as AIDS cachexia, cancer cachexia, and cardiac cachexia; cancer; cardiomyopathy; chronic kidney or heart failure; chronic obstructive pulmonary disease (COPD); denervation; diabetes; emphysema; end stage renal failure; frailty; HIV infection; inactivity; leprosy; malnutrition; muscle atrophies such as Post-Polio Muscle Atrophy (PPMA) or X-linked spinal-bulbar muscular atrophy (SBMA); muscular dystrophies, such as Duchemie Muscular Dystrophy, myotonic dystrophy, Becker's muscular dystrophy (benign pseudohypertrophic muscular dystrophy), limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), congenital muscular dystrophy, Oculopharyngeal Muscular Dystrophy (OPMD), distal muscular
  • muscle wasting In addition, other circumstances and conditions are linked to and can cause muscle wasting. These include chronic lower back pain, advanced age, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, central nervous system (CNS) damage, microgravity, peripheral nerve damage, spinal cord damage, chemical damage, bums, disuse, deconditioning that occurs when a limb is immobilized, long term hospitalization due to illness or injury, and alcoholism. Muscle wasting, if left unabated, can have dire health consequences. For example, the changes that occur during muscle wasting can lead to a weakened physical state that is detrimental to an individual's health, resulting in increased susceptibility to infraction and poor performance status. In addition, muscle wasting is a strong predictor of morbidity and mortality in patients suffering from cachexia and AIDS.
  • Muscle wasting due to infectious pathologies include muscle wasting disorders due to infection with coxsackie virus, enterovirus, Epstein-Barr virus, herpes zoster, HIV, influenza, mycobacteria, rickettsia, schistosoma, trichinella or trypanosomes.
  • the loss of muscle mass that occurs during muscle wasting can be characterized by a breakdown or degradation of muscle protein, such as by muscle protein catabolism.
  • Protein catabolism occurs because of an unusually high rate of protein degradation, an unusually low rate of protein synthesis, or a combination of both. Protein catabolism or depletion, whether caused by a high degree of protein degradation or a low degree of protein synthesis, leads to a decrease in muscle mass and to muscle wasting.
  • Muscle wasting also is associated with advanced age. It is believed that general weakness in old age is due to muscle wasting. As the body ages, an increasing proportion of skeletal muscle is replaced by fibrous tissue. The result is a significant reduction in muscle power, performance and endurance. Long term hospitalization due to illness or injury, or muscle disuse that occurs, for example, when a limb is immobilized, also can lead to muscle wasting. Patients suffering injuries, chronic illnesses, burns, trauma or cancer, who are hospitalized for long periods of time, often exhibit a long-lasting unilateral muscle wasting.
  • anabolic steroids have demonstrated the ability to increase weight and muscle mass in some patients with muscle wasting, such as in cancer patients.
  • administration of anabolic steroids can result in unwanted androgenic side effects, including development of oily skin or acne, as well as masculinization in women and prostate stimulation in men.
  • SARMs have demonstrated efficacy for attenuating muscle wasting across a range of disorders (e.g., see Allen et al Endocrine 32(1): 41 -51 (2007); Lynch et al, Pharmacology & Therapeutics 1 13(3): 461-487 (2007); Gao et al, Endocrinology 146(1 1): 4887-4897 (2005); Lynch, Expert Opinion on Emerging Drugs 9(2): 345-361 (2004); U.S. Pat.
  • SARMs generally demonstrate predominately anabolic activity in muscle and bone with minimal androgenic effects in most other tissues.
  • the compounds provided herein are useful for treating muscle wasting.
  • the compounds provided herein are useful for treating sarcopenia. 2.
  • Muscle tone and strength Androgen receptor agonists are known to have a beneficial effect on muscle tone and strength (e.g., see Gao et al, Endocrinology 146(1 1 ): 4887-4897 (2005),
  • the compounds provided herein can stimulate muscle growth and can be used for treatment of sarcopenia and frailty.
  • one or more compounds of formula I, II or III are used to enhance muscle tone in a subject.
  • one or more compounds of formula I, II or III are used to improve muscle strength in a subject. 3. Osteoporosis
  • Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue leading to bone fragility and an increased susceptibility to fractures of the hip, spine, ribs and wrist.
  • Loss of estrogens or androgens causes an imbalance between resorption and formation of bone by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts.
  • Loss of androgens also may induce bone loss by increasing the rate of bone remodeling (Lindberg et al, Minerva Endocrinol. 30(1): 15-25 (2005)).
  • the beneficial effects of androgens on bone in postmenopausal osteoporosis are described in art (e.g., see Hofbauer et al., Eur. J.
  • Androgens also play an important role in bone metabolism in men (e.g., see Anderson et al., Bone 18: 171- 177 (1996). Androgen receptor modulator compounds also have been shown to improve bone strength in a rat model of post-menopausal osteoporosis (e.g., see Martinborough et al., J Med Chem. 50(21): 5049-5052 (2007)). Osteoporosis can result from androgen deprivation.
  • the compounds provided herein can activate the function of the androgen receptor in a mammal, and in particular to activate the function of the androgen receptor in bone. Methods for assessing osteoporosis and osteopenia are well known in the art.
  • a subject's bone mineral density (BMD), measured by densitometry and expressed in g/cm 2 , is compared with a "normal value," which is the mean BMD of sex -matched young adults at their peak bone mass, yielding a "T-score.”
  • a score of 0 means the subject's BMD is equal to the norm for a healthy young adult. Differences between the BMD of a subject and that of the healthy young adult norm are measured in standard deviation units (SDs).
  • SDs standard deviation units
  • a T-score between +1 and -1 is considered normal or healthy.
  • a T-score between -1 and -2.5 indicates low bone mass and is indicative of osteopenia.
  • a T-score of -2.5 or lower is indicative of osteoporosis.
  • the compounds provided herein are useful for the treatment of osteoporosis in women and men as a monotherapy or in combination with inhibitors of bone resorption, such as bisphosphonates, estrogens, SERMs, cathepsin inhibitors, GJ V /3 3 integrin receptor antagonists, calcitonin, and proton pump inhibitors. They also can be used with agents that stimulate bone formation, such as parathyroid hormone or analogs thereof.
  • a compound provided herein is administered in combination with an effective amount of at least one bone-strengthening agent chosen from among estrogen and estrogen derivatives, alone or in combination with progestin or progestin derivatives; bisphosphonates; anti-estrogens; selective estrogen receptor modulators (SERMs); ovft integrin receptor antagonists; cathepsin inhibitors; proton pump inhibitors; PPAR ⁇ inhibitors; calcitonin; and osteoprotegerin.
  • exemplary estrogen and estrogen derivatives include 170-estradiol, estrone, conjugated estrogen (PREMARIN ® ), equine estrogen and 17/3-ethynyl estradiol.
  • the estrogen or estrogen derivative can be used alone or in combination with a progestin or progestin derivatives.
  • exemplary progestin derivatives include norethindrone and medroxy-progesterone acetate.
  • Other estrogen receptor modulators are known in the art (e.g., see U.S. Pat. Nos. 7,151,196, 7,157,604, 7,138,426).
  • Exemplary bisphosphonate compounds which can be used in combination with a compound provided herein include alendronate (see U.S. Pat. Nos. 5,510,517, and 5,648,491), [(cycloheptylamino)-methylene]-bis-phosphonate (incadronate) (see U.S. Pat. No. 4,970,335); (dichloromethylene)-bis-phosphonic acid (clodronic acid) and the disodium salt (clodronate) (see Quimby et al, J. Org.
  • the bisphosphonate is chosen from among alendronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, olpadronate, pamidronate, piridronate, risedronate, tiludronate, zoledronate, and mixtures and pharmaceutically acceptable salts thereof.
  • SERMs or selective estrogen receptor modulators
  • SERMs are agents known in the art to prevent bone loss by inhibiting bone resorption via pathways believed to be similar to those of estrogens ⁇ e.g., see Goldstein et al, Human Reproduction Update 6: 212- 224 (2000); Lufkin et al, Rheumatic Disease Clinics of North America 27: 163-185 (2001), Chan, Semin Oncol. 29(3 Suppl 1 1): 129-133 (2002), Jordan, Cancer Research 61 : 5683-5687 (2001) and Miller & Med, Chapter 15, "Targeting the Estrogen Receptor with SERMs" in Ann. Rep. Med. Chem. 36: 149-158 (2001)).
  • Exemplary SERMs include arzoxifene, clomiphene, droloxifene, enclomiphene, idoxifene, lasofoxifene, levormeloxifene, nafoxidine, raloxifene, tamoxifen, toremifene, zuclomiphene, and salts thereof (see, e.g., U.S. Pat. Nos. 4,729,999, 4,894,373 and 5,393,763).
  • Ofyft Integrin receptor antagonists suppress bone resorption and can be employed in combination with the SARMs provided herein for the treatment of bone disorders including osteoporosis.
  • Antagonists of the ⁇ v j3 3 integrin receptor are known in the art ⁇ e.g., see U.S. Pat. Nos.
  • Cathepsin is a cysteine protease and is described in U.S. Pat. Nos. 5,501,969 and 5,736,357. Cysteine proteases, such as cathepsins, are linked to a number of disease conditions, including arthritis, bone remodeling, inflammation and tumor metastasis. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis. Examples of cathepsin inhibitors are described in Deaton, Current Topics in Medicinal Chemistry 5(16): 1639-1675 (2005), in U.S. Pat. Nos. 7,279,478, 7,279,472, 7,1 12,589 and 7,012,075, and in WO 01/49288 and WO 01/77073.
  • Proton pump inhibitors such as osteoclast vacuolar ATPase inhibitors
  • SARMs provided herein.
  • the proton ATPase found on the apical membrane of the osteoclast has been reported to play a significant role in the bone resorption process and is a target for the design of inhibitors of bone resorption, thereby useful for the treatment and prevention of osteoporosis and related metabolic diseases ⁇ e.g., see Niikura, Drug News Perspect. 19(3): 139-44 (2006), Visentin et al., J Clin Invest 106(2): 309-318 (2000) and Niikura et al., Br J of Pharmacology 142: 558-566 (2004)).
  • Exemplary inhibitors include bafilomycin Al, SB242784, FR167356, FR177995, FR202126, FR133605 and NiK-12192 [4-(5,6- dichloro-lH-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide] (Petrangolini et al., J Pharmacol Exp Ther 318 (3): 939-946 (2006).
  • Activators of the peroxisome proliferator-activated receptor gamma are known in the art inhibit osteoclast-like cell formation and bone resorption (e.g. , see Okazaki et al., Endocrinology 140: 5060-5065 (1999)).
  • Exemplary PPAR ⁇ activators include the glitazones, such as ciglitazone, darglitazone, englitazone, troglitazone, pioglitazone, rosiglitazone, and BRL 49653, the thiazolidinediones (see, e.g., Yki-Jarvinen, New Eng J Med 351(1 1): 1 106-1 1 18 (2004), netoglitazone, 15- deoxy- ⁇ i 2 ,i 4 -prostaglandin J 2 and analogs, derivatives, and pharmaceutically acceptable salts thereof.
  • glitazones such as ciglitazone, darglitazone, englitazone, troglitazone, pioglitazone, rosiglitazone, and BRL 49653, the thiazolidinediones (see, e.g., Yki-Jarvinen, New Eng J Med 351(1 1): 1 106-1
  • therapeutically effective amounts of a compound of Formula I, II or III alone or in combination with another active agent is administered to the mammal to treat a condition or disorder selected from among osteoporosis, osteopenia, glucocorticoid-induced osteoporosis and bone fracture. 4. Prostate Disease and Prostate Cancer
  • the compounds provided herein can be used for treatment of prostate disease, such as prostate cancer and benign prostatic hyperplasia (BPH).
  • compounds provided herein can block or inhibit (antagonize) the function of the androgen receptor in the prostate of a male individual.
  • the standard treatment is androgen receptor- blockade, usually in combination with LHRH superagonists, which suppresses both adrenal and testicular testosterone.
  • LHRH superagonists which suppresses both adrenal and testicular testosterone.
  • the rationale of this approach is that early prostate cancer usually depends on androgens for growth.
  • the mechanism of clinically utilized anti-androgens is thought to involve blockade of the AR by binding to it and/or by interference with binding of the AR to the DNA.
  • Anti-androgens are thought to involve blockade of the AR by binding to it and/or by interference with binding of the AR to the DNA.
  • anti-androgens used in the treatment of prostate cancer are flutamide and nilutamide (e.g., see U.S. Pat. No. 7,018,993).
  • the properties and usefulness of these anti-androgens are known in the art (e.g., see Neri, J. Drug Develop. 1 (Suppl.): 5-9 (1987), Neri et al, Urology 34 (4 Suppl.): 19-21 and 46-56 (1989), Neri et al., J Steroid Biochem. 6(6): 815-819 (1975), Neri et al, Anticancer Res. 9(1): 13-16 (1989), Jackson et al, Anticancer Res.
  • compounds and/or compositions provided herein are therapeutically effective for treating prostate cancer.
  • prostate cancer is dependant on androgens.
  • Such androgen dependent prostate cancer is typically amenable to treatment by androgen receptor antagonists and/or androgen receptor partial agonists.
  • the prostate cancer is androgen dependant prostate cancer.
  • the prostate cancer is androgen independent prostate cancer.
  • the prostate cancer is androgen independent, but androgen receptor dependant prostate cancer.
  • the compounds provided herein are tissue selective AR modulators. In some embodiments, the compounds provided herein are tissue selective AR antagonists. Tissue selective AR antagonists in the prostate that lack antagonistic action in bone and muscle are known in the art to be useful agents for the treatment of prostate cancer, either alone or as an adjunct to traditional androgen deprivation therapy (see, e.g., Stoch et al, J. Clin. Endocrin. Metab. 86: 2787-2791 (2001)). Thus, compounds provided herein that are tissue selective AR antagonists in the prostate that lack antagonistic action in bone and muscle are useful agents for the treatment of prostate cancer, either alone or as an adjunct to traditional androgen deprivation therapy.
  • Hematopoietic conditions and disorders Hematopoiesis is a constant process in which specialized blood cells, such as erythrocytes, B and T lymphocytes, platelets, granulocytes, monocytes, and macrophages, are generated from hematopoietic stem cells.
  • specialized blood cells such as erythrocytes, B and T lymphocytes, platelets, granulocytes, monocytes, and macrophages.
  • hematopoietic stem cells A number of undesired hematopoietic conditions can occur in a subject. These include inadequate production of, or increased destruction of, platelets, red blood cells or white blood cells.
  • aplastic anemia refractory anemias
  • idiopathic thrombocytopenia purpura immune thrombocytopenias
  • leukemia myelodysplastic and preleukemia syndromes
  • megaloblastic anemia and platelet deficiency myeloproliferative disorders and uremia.
  • Hematopoietic cytokines such as erythropoietin
  • Androgens are known in the art to stimulate renal hypertrophy and erythropoietin (EPO) production.
  • Androgens have been used to treat anemia caused by chronic renal failure.
  • androgens increase serum EPO levels in anemic patients with non-severe aplastic anemia and myelodysplastic syndromes.
  • the selective androgen modulator compounds provided herein can be used to treat certain hematopoietic disorders including aplastic anemia, refractory anemias, idiopathic thrombocytopenia purpura, immune thrombocytopenias, leukemia, preleukemia/myelodysplastic syndromes, megaloblastic anemia and platelet deficiency, myeloproliferative disorders and uremia.
  • a compound of formula I, II or III is used to increase the number of blood cells, such as red blood cells and platelets in a subject.
  • Neurodegenerative diseases and disorders can be used in the treatment of neurodegenerative diseases, such as Alzheimer's disease.
  • androgens and selective androgen receptor modulators can be useful in preventing the onset or delaying the progression of Alzheimer's disease in male patients (e.g., see Fuller et al., J Alzheimer's Dis. 12(2): 129-142 (2007)).
  • androgen receptor agonists have therapeutic value in the treatment of neurodegenerative diseases such as Alzheimer's disease (e.g., see Hammond et al., J. Neurochem. 77: 1319-1326 (2001)).
  • Androgen receptor agonists such as testosterone have been shown to reduce secretion of /3-amyloid peptides characteristic of Alzheimer's disease and can therefore be used in the treatment of Alzheimer's disease (Gouras et al, Proc. Nat. Acad. Sci. USA 97: 1202-1205 (2000)). Androgen receptor agonists also have been shown to inhibit hyperphosphorylation of proteins implicated in the progression Alzheimer's disease (e.g., see Papasozomenos, Proc. Nat. Acad. Sci. USA 99: 1 140-1 145 (2002)).
  • apoE4 contributes to cognitive decline in Alzheimer's disease by reducing AR levels in the brain, and that stimulating AR-dependent pathways can reverse apoE4-induced cognitive deficits (e.g., see Raber et al, J Neurosci. 22(12): 5204-5209 (2002).
  • the compounds provided herein are useful in the treatment of Alzheimer's disease and other neurodegenerative disorders.
  • androgen receptor modulators can be useful in treating cognitive impairment (see Pfankuch et al, Brain Res. 1053(1-2): 88-96 (2005) and Wisniewski, Horm. Res. 58: 150-155 (2002)).
  • Obesity has been associated with alterations in androgen secretion, transport, metabolism, and action, with obese men displaying a decrease of testosterone levels with increasing body weight and obese women, especially those with abdominal obesity, displaying a condition of functional hyperandrogenism (e.g., see Pasquali, Fertil Steril. 85(5): 1319- 1340 (2006). It has been demonstrated in the art that androgen administration reduces subcutaneous and visceral fat in obese patients (e.g., see Lovejoy et al, Int. J. Obesity 19: 614-624 (1995) and Lovejoy et al., J. Clin. Endocrinol. Metab. 81 : 2198- 2203 (1996)).
  • the SARMs provided herein can be beneficial in the treatment of obesity.
  • the compounds provided herein that are AR agonists are used to treat a male subject with abdominal adiposity.
  • the compounds provided herein that are AR antagonists are used to treat a female subject with abdominal obesity. 8. Insulin Disorders and Diabetes In vivo studies have shown that the androgen receptor plays a key role in the development of insulin resistance, which may contribute to the development of type 2 diabetes and cardiovascular disease (e.g., see Lin et al., Diabetes 54(6): 1717-1725 (2005). Androgen receptor agonists also can have therapeutic value against metabolic syndrome (insulin resistance syndrome, syndrome X), particularly in men.
  • Testosterone is used as a treatment for sexual dysfunction in hypogonadal patients (Yassin et al., World Journal of Urology 24: 6: 639 (2006). It is known in the art that androgen deficiency in women is clinically often associated with a loss of libido and energy ⁇ e.g., ArIt, Eur J Endocrinol 154(1): 1-11 (2006) and Rivera- WoIl et al, Human Reproduction Update 10(5): 421 (2004)). Low androgen levels have been shown to contribute to the decline in sexual interest in many women during their later reproductive years (Davis, Clin. Endocrinol. Metab. 84: 1886-1891 (1999)).
  • the compounds provided herein can be useful in the treatment of sexual dysfunction.
  • the compounds provided herein are useful for hormone replacement therapy in hypogonadic (androgen deficient) men.
  • compounds provided herein are useful in activating the function of the androgen receptor in bone and/or muscle tissue and blocking or inhibiting the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual.
  • the compounds provided herein are used to attenuate or block the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual induced by AR agonists without effecting hair- growing skin or vocal cords.
  • the compounds provided herein are used to activate the function of the androgen receptor in bone and/or muscle tissue, but not in organs which control blood lipid levels (e.g., the liver). 10.
  • the compounds provided herein also are used, alone or in combination, to treat or prevent arthritic conditions, such as Behcet's disease, bursitis, tendonitis, CPPD deposition disease, carpal tunnel syndrome, Ehlers-Danlos syndrome, fibromyalgia, gout, infectious arthritis, inflammatory bowel disease, juvenile arthritis, lupus erythematosus, Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis imperfecta, osteonecrosis, polyarteritis, polymyalgia rheumatica, psoriatic arthritis, Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, Reiter's syndrome, rheumatoid arthritis, scleroderma and Sjogren's syndrome.
  • arthritic conditions such as Behcet's disease, bursitis, tendonitis, CPPD deposition disease, carpal tunnel syndrome, Ehlers-Danlos syndrome, fibro
  • the method including administering a therapeutically effective amount of a compound of any of Formulae I, II or III in an amount effective for the treatment or prevention of an arthritic condition or an inflammatory disorder.
  • the method is for the treatment or prevention of osteoarthritis, which includes administering a therapeutically effective amount of a compound of any of Formulae I, II or III in an amount effective for the treatment or prevention of osteoarthritis.
  • High doses of testosterone and other anabolic steroids have the ability to reduce cholesterol and to reduce HDL, often greater that 60%, 65%, 70%, 75% and 80%.
  • a compound of formula I, II or III is used to reduce total cholesterol, LDL, HDL, VLDL, and/or triglycerides.
  • administration of a compound of formula I, II or III can be used to reduce levels of total cholesterol, LDL, VLDL, triglycerides and/or HDL, while the LDL/HDL ratio remains in the normal range.
  • Contraception Hormonal contraception is known in the art.
  • hormonal male contraceptive methods provide pregnancy protection by means of spermatogenic suppression or inhibition, generally by the suppression of gonadotropins (e.g., see Pasqualotto et al, Rev Hosp Clin Fac Med Sao Paulo 58(5): 275-283 (2003), Ly et al, Hum Reprod. 20(6): 1733-1740 (2005) and Brady et al, Hum Reprod. 19(1 1): 2658-2667 (2004)).
  • an androgen receptor modulator alone, or in combination with other androgens, such as 19- nortestosterone, 7 ⁇ -methyl-19-nortestosterone (MENT) and 5 ⁇ -dihydrotestosterone
  • testosterone in combination with an anti-androgen ⁇ e.g., see Turner et al, J Clin Endocrinol Metab 88(10): 4659-4667 (2003).
  • Hormonally mediated suppression of ovulation in women using synthetic androgens is known in the art, but their use is limited because of adverse effects, including weight gain, decreased high-density lipoprotein cholesterol, and in some instances, facial hair growth and acne ⁇ e.g., see Johnson, Clin Obstet Gynecol. 41 : 405-421 (1998) and Sulak, Am J Manag Care 1 1 : S492-S497 (2005).
  • the selective androgen modulating compounds provided herein are useful for providing contraception while minimizing adverse side effects associated with steroidal androgens.
  • Tissue-selective AR antagonists also can treat polycystic ovarian syndrome in postmenopausal women (Eagleson et al., J. Clin. Endocrinol. Metab. 85: 4047-4052 (2000)).
  • a compound of formula I, II or III is used to treat a postmenopausal condition in a female subject.
  • the postmenopausal condition is selected from among hot flashes, loss of libido, decreased feelings of well being and fatigue.
  • a compound of formula I, II or III is used to treat hot flashes in a female subject.
  • a compound of formula I, II or III is used to treat hypoactive sexual desire disorder in a postmenopausal female subject.
  • the compounds of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof can be provided as combinations with other therapeutic agents or in pharmaceutical compositions.
  • the pharmaceutical compositions provided herein include therapeutically effective amounts of one or more of the selective androgen receptor activity modulators provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of diseases or disorders associated with androgen receptor activity.
  • the compositions include one or more compounds provided herein.
  • the compositions are formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transderma
  • a pharmaceutical composition including one or more compounds provided herein is prepared using known techniques, including, but not limited to, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • effective concentrations of one or more compounds or pharmaceutically acceptable derivatives is (are) mixed with a suitable pharmaceutical carrier or vehicle.
  • the compounds can be derivatized as the corresponding salts, esters, enol ethers or esters, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above.
  • the concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders associated with androgen activity or in which androgen activity is implicated.
  • compositions are formulated for single dosage administration.
  • the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated.
  • Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients.
  • Liposomal suspensions including tissue-targeted liposomes, such as tumor-targeted liposomes, also can be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) can be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask.
  • MLVs multilamellar vesicles
  • a solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed.
  • PBS phosphate buffered saline lacking divalent cations
  • One or more than one of the compounds provided herein is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated.
  • concentration of the one or more than one compounds provided herein in the pharmaceutical composition will depend on absorption, inactivation and excretion rates of the compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with androgen activity or in which androgen activity is implicated, as described herein.
  • the effective amount of a compound provided herein can be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 100 mg/kg of body weight of active compound per day, which can be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
  • the daily dosage of a compound provided herein can be varied over a wide range from about or 0.01 to about or 1000 mg per adult human per day.
  • dosages can range from about or 0.1 to about or 200 mg/day.
  • the dosage can range from 0.2 mg to 20 mg per day.
  • the dosage can range from 0.5 mg to 10 mg per day.
  • the daily dosage can be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg, 5.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg, 8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, 9.75 mg, 10 mg.
  • compositions can be provided in the form of unit dosages such as tablets or capsules or liquids including from about or 0.01 to about or 1000 mg, such as for example, 0.01, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 400, 500, 750, 800, 850, 900, 950 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • unit dosages such as tablets or capsules or liquids including from about or 0.01 to about or 1000 mg, such as for example, 0.01, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 400, 500, 750, 800, 850, 900
  • the compositions can be provided in the form of unit dosages such as tablets or capsules or liquids including from about or 0.01 to about or 1000 ⁇ g, such as for example, 0.01 , 0.05, 0.075, 0.1 , 0.25, 0.5, 0.75, 1 , 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 and 1000 micrograms of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • unit dosages such as tablets or capsules or liquids including from about or 0.01 to about or 1000 ⁇ g, such as for example, 0.01 , 0.05, 0.075, 0.1 , 0.25, 0.5, 0.75, 1 , 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180,
  • the pharmaceutical composition including one or more than one compound provided herein can be administered at once, or can be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values also can vary with the severity of the condition to be alleviated.
  • compositions include acids, bases, enol ethers and esters, salts, esters, hydrates, solvates and prodrug forms.
  • the derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.
  • compositions described herein or pharmaceutically acceptable derivatives or prodrugs thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions.
  • a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions.
  • One or more than one compound provided herein is/are included in an amount effective for ameliorating one or more symptoms of, or for treating or preventing diseases or disorders associated with androgen receptor activity or in which androgen receptor activity is implicated, as described herein.
  • concentration of the one or more than one compound in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.
  • compositions are intended to be administered by a suitable route, including orally in the form of capsules, tablets, granules, powders or liquid formulations including syrups; parenterally, such as subcutaneously, intravenously, intramuscularly, with intersternal injection or infusion techniques (as sterile injectable aqueous (aq.) or non-aqueous solutions or suspensions); nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally, such as in the form of suppositories; liposomally; and locally.
  • the compositions can be in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
  • administration of the formulation includes parenteral and oral modes of administration, hi one embodiment, the compositions are administered orally.
  • the pharmaceutical compositions provided herein including one or more compounds provided herein is a solid (e.g., a powder, tablet, and/or capsule).
  • a solid pharmaceutical composition including one or more compounds provided herein is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, gums, lubricants, binders, and disintegrating agents.
  • a pharmaceutical composition including one or more compounds provided herein is formulated as a depot preparation. Certain of such depot preparations are typically longer acting than non-depot preparations.
  • such preparations are administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • depot preparations are prepared using suitable polymeric or hydrophobic materials (for example, an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical composition including one or more compounds provided herein includes a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those including hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical composition including one or more compounds provided herein (active ingredient) includes one or more tissue-specific delivery molecules designed to deliver the pharmaceutical composition to specific tissues or cell types.
  • tissue-specific delivery molecules designed to deliver the pharmaceutical composition to specific tissues or cell types.
  • pharmaceutical compositions include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical composition including one or more compounds provided herein includes a co-solvent system.
  • co-solvent systems include, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • a non-limiting example of such a co- solvent system is the VPD co-solvent system, which is a solution of absolute ethanol including 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300.
  • co-solvent systems can be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components can be varied: for example, other surfactants can be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol can be varied; other biocompatible polymers can replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides can substitute for dextrose.
  • solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediamine- tetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent
  • antimicrobial agents such as benzyl alcohol and methyl parabens
  • antioxidants such as ascorbic acid and sodium
  • Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
  • methods for solubilizing compounds can be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as surfactants that include polyoxyethylene derivatives of sorbitan monolaurate, such as TWEEN or polysorbate surfactants, or dissolution in aqueous sodium bicarbonate.
  • cosolvents such as dimethylsulfoxide (DMSO)
  • surfactants such as surfactants that include polyoxyethylene derivatives of sorbitan monolaurate, such as TWEEN or polysorbate surfactants
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate.
  • Derivatives of the compounds, such as prodrugs of the compounds also can be used in formulating effective pharmaceutical compositions.
  • a pharmaceutical composition including one or more compounds provided herein includes a sustained release system.
  • a sustained-release system is a semipermeable matrix of solid hydrophobic polymers.
  • sustained release systems can, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
  • the resulting mixture upon mixing or addition of the compound(s), can be a solution, suspension or emulsion. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and can be empirically determined.
  • compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil- water emulsions including suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically active compounds and derivatives thereof are typically formulated and administered in unit dosage forms.
  • the composition can include in addition to the one or more than one compound provided herein other ingredients, such as, but not limited to, a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acacia, gelatin, glucose, molasses, polyvinylpyrrolidone, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acacia, gelatin, glucose, molasses, polyvinylpyrroli
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols and ethanol, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols and ethanol
  • the pharmaceutical composition to be administered also can include minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, or pH buffering agents, for example, acetate or sodium citrate, or cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate.
  • composition or formulation to be administered will, in any event, include a quantity of the active compound in an amount sufficient to alleviate the symptoms of the treated subject.
  • Dosage forms or compositions can be prepared to include one or more than one compound provided herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier.
  • a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium croscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • excipients such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium croscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art
  • compositions can include 0.001 %-l 00% active ingredient, in one embodiment 0.1-85%, in another embodiment 75-95%. In some embodiments, the compositions include 1-10% active ingredient. In some embodiments, the compositions include 10-25% active ingredient. In some embodiments, the compositions includes 15-35% active ingredient. In some embodiments, the compositions include 40-60% active ingredient. In some embodiments, the compositions include 50-75% active ingredient.
  • the active ingredient is present at 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%
  • the compounds can be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
  • exemplary compositions for topical administration include a topical carrier such as a mineral oil gelled with polyethylene (e.g. , PLASTIB ASE ® ).
  • compounds provided herein used in the pharmaceutical compositions can be provided as pharmaceutically acceptable salts with pharmaceutically compatible counter-ions.
  • Pharmaceutically compatible salts can be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, citric, ascorbic, butyric, lactic, tartaric, malic, fumaric, succinic and valeric.
  • the pharmaceutical compositions include one or more than one compound provided herein in a therapeutically effective amount.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • compositions can include in addition to the one or more than one compound provided herein other active compounds to obtain desired combinations of properties.
  • the compounds provided herein, or pharmaceutically acceptable derivatives or prodrugs thereof as described herein also can be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases or disorders associated with androgen receptor activity or in which androgen receptor activity is implicated. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.
  • a pharmaceutical composition including one or more compounds provided herein is formulated as a prodrug.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug can be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug can have improved solubility compared to the corresponding active form.
  • a prodrug is an ester.
  • such prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid.
  • a prodrug includes a short peptide (polyamino acid) bound to an acid group. In certain of such embodiments, the peptide is metabolized to form the corresponding active form.
  • a pharmaceutical composition including one or more compounds provided herein is useful for treating a conditions or disorder in a mammalian, and particularly in a human subject.
  • Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous).
  • pharmaceutical compositions are administered to achieve local rather than systemic exposures.
  • pharmaceutical compositions can be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound provided herein.
  • a pharmaceutical composition including one or more compounds provided herein is administered in the form of a dosage unit (e.g., tablet, capsule, pill, injection, bolus).
  • dosage units include a selective androgen receptor modulator provided herein in a dose from about or 0.01 ⁇ g/kg of body weight to about or 50 mg/kg of body weight.
  • dosage units include a selective androgen receptor modulator in a dose from about or 0.05 ⁇ g/kg of body weight to about or 40 mg/kg of body weight.
  • such dosage units include a selective androgen receptor modulator in a dose from about or 0.1 ⁇ g/kg of body weight to about or 30 mg/kg of body weight.
  • such dosage units include a selective androgen receptor modulator in a dose from about or 0.5 ⁇ g/kg of body weight to about or 25 mg/kg of body weight. In certain embodiments, such dosage units include a selective androgen receptor modulator in a dose from about or 1 ⁇ g/kg of body weight to about or 20 mg/kg of body weight. In certain embodiments, such dosage units include a selective androgen receptor modulator in a dose from about or 2 ⁇ g/kg of body weight to about or 15 mg/kg of body weight. In certain embodiments, such dosage units include a selective androgen receptor modulator in a dose from about or 10 ⁇ g/kg of body weight to about or 5 mg/kg of body weight.
  • such dosage units include a selective androgen receptor modulator provided herein in a dose from about or 0.01 mg/kg of body weight to about or 1 mg/kg of body weight. In certain embodiments, such dosage units include a selective androgen receptor modulator in a dose from about or 0.05 mg/kg of body weight to about or 0.1 mg/kg of body weight.
  • such dosage units include a selective androgen receptor modulator in a dose from about or 0.001 ⁇ g/kg of body weight to about or 100 ⁇ g/kg of body weight. In certain embodiments, such dosage units include a selective androgen receptor modulator in a dose from about or 0.01 ⁇ g/kg of body weight to about or 10 ⁇ g/kg of body weight. In certain embodiments, such dosage units include a selective androgen receptor modulator in a dose from about or 0.1 ⁇ g/kg of body weight to about or 1 ⁇ g/kg of body weight. An approximate average adult body weight is 70 kg.
  • a dose of 0.1 ⁇ g/kg of body weight is equivalent to 7 ⁇ g
  • a dose of 1 ⁇ g/kg of body weight is equivalent to 70 ⁇ g
  • a dose of 10 ⁇ g/kg of body weight is equivalent to 700 ⁇ g or 0.7 mg
  • a dose of 0.1 mg/kg of body weight is equivalent to 7 mg.
  • pharmaceutical compositions are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the subject, and tolerance for the pharmaceutical composition.
  • a pharmaceutical composition provided herein is administered for a period of continuous therapy.
  • a pharmaceutical composition provided herein can be administered over a period of days, weeks, months, or years.
  • Dosage amount, interval between doses, and duration of treatment can be adjusted to achieve a desired effect.
  • dosage amount and interval between doses are adjusted to maintain a desired concentration of compound in a subject.
  • dosage amount and interval between doses are adjusted to provide plasma concentration of a compound provided herein at an amount sufficient to achieve a desired effect.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • pharmaceutical compositions provided herein are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.
  • compositions for oral administration are provided.
  • oral pharmaceutical dosage forms are either solid, gel or liquid.
  • the solid dosage forms are tablets, capsules, granules, and bulk powders.
  • Types of oral tablets include compressed, chewable lozenges and tablets which can be enteric coated, sugar coated or film coated.
  • Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
  • the formulations are solid dosage forms, such as capsules or tablets.
  • the tablets, pills, capsules, troches and other solid dosage forms can include any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
  • compositions for oral administration are push fit capsules made of gelatin.
  • Certain of such push fit capsules include one or more compounds provided herein in admixture with one or more fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more compounds provided are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added.
  • compositions are prepared for buccal administration. Certain of such pharmaceutical compositions are tablets or lozenges formulated in conventional manner. In some embodiments, the compositions are formulated as dissolvable films, such as those made with pullulan or described in the art (e.g., see U.S. Pat. Nos. 6,596,298, 7,067,116, 7,182,964 and 7,241,41 1).
  • binders for use in the compositions provided herein include microcrystalline cellulose, gum tragacanth, glucose solution, gum arabic, gelatin solution, sucrose and starch paste.
  • Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • Glidants include, but are not limited to, colloidal silicon dioxide.
  • Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, sodium alginate, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • Sweetening agents include sucrose, lactose, mannitol, xylitol and artificial sweetening agents such as saccharin.
  • Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate, including spray dried natural and artificial flavors.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether.
  • Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the compound can be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition also can be formulated in combination with an antacid or other such ingredient.
  • dosage unit form When the dosage unit form is a capsule, it can include, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can include various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the compounds also can be administered as a component of an elixir, suspension, syrup, wafer, sprinkle or chewing gum.
  • a syrup can include, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active materials also can be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers (acid reducers), and diuretics.
  • Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
  • Enteric coated tablets because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
  • Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
  • Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned.
  • Coloring agents also can be used in the above dosage forms.
  • Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Aqueous solutions include, for example, elixirs and syrups.
  • Emulsions are either oil-in-water or water-in-oil.
  • Elixirs are clear, sweetened, hydroalcoholic preparations.
  • Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and can include a preservative.
  • An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid.
  • Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives.
  • Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents.
  • Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
  • Solvents include glycerin, sorbitol, ethyl alcohol and syrup.
  • preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • emulsifying agents include gelatin, gum arabic, gum tragacanth, xanthan gum, propylene glycol alginate, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • Suspending agents include xanthan gum, sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Diluents include lactose and sucrose.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • Organic acids include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
  • the solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the solution e.g., for example, in a polyethylene glycol
  • a pharmaceutically acceptable liquid carrier e.g., water
  • liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Other useful formulations include those set forth in U.S. Patent Nos. Re 28,819 and 4,358,603.
  • such formulations include, but are not limited to, those including a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1 ,2-dimethoxy-methane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.
  • BHT butyl
  • formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal.
  • Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol.
  • Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.
  • tablets and capsules formulations can be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions can include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins.
  • high molecular weight excipients such as celluloses and microcrystalline celluloses (AVICEL ® ) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ ® ); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934 ® ).
  • Lubricants, glidants, flavors, coloring agents and stabilizers also can be added for ease of fabrication and use.
  • a pharmaceutical composition for oral administration is formulated by combining one or more compounds provided herein with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers enable compounds provided herein to be formulated in dosage forms, such as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, for oral ingestion by a subject.
  • pharmaceutical compositions for oral use are obtained by mixing one or more compounds provided herein and one or more solid excipient.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical compositions are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate
  • dragee cores are provided with coatings.
  • concentrated sugar solutions can be used, which can optionally include gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to tablets or dragee coatings.
  • a daily dosage regimen for a subject includes an oral dose of between 0.1 ⁇ g and 2000 mg of a compound provided herein. In certain embodiments, a daily dosage regimen for a subject includes an oral dose of between 1 ⁇ g and 500 mg of a compound provided herein. In certain embodiments, a daily dosage regimen for a subject includes an oral dose of between 10 ⁇ g and 100 mg of a compound provided herein.
  • a daily dosage regimen for a subject includes an oral dose selected from among 0.01, 0.05, 0.075, 0.1 , 0.25, 0.5, 0.75, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 180, 190, 200, 225, 250, 300, 400, 500, 750, 800, 850, 900, 950 and 1000 milligrams of a compound provided herein.
  • a daily dosage regimen is administered as a single daily dose.
  • a daily dosage regimen is administered as two, three, four, or more than four doses. 2. Injectables, solutions and emulsions
  • the pharmaceutical composition is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • Parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously also is contemplated herein.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, mannitol, 1,3-butanediol, Ringer's solution, an isotonic sodium chloride solution or ethanol.
  • the pharmaceutical compositions to be administered also can include minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, mono-or diglycerides, fatty acids, such as oleic acid, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene- terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethyl- siloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene
  • parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations.
  • Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
  • the solutions can be either aqueous or nonaqueous.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions including thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • PBS physiological saline or phosphate buffered saline
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Isotonic agents include sodium -chloride and dextrose.
  • Buffers include phosphate and citrate.
  • Antioxidants include sodium bisulfate.
  • Local anesthetics include procaine hydrochloride.
  • Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxy- propyl methylcellulose and polyvinylpyrrolidone.
  • Emulsifying agents include Polysorbate 80 (TWEEN ® 80).
  • a sequestering or chelating agent of metal ions include EDTA.
  • Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect.
  • the exact dose depends on the age, weight and condition of the subject or animal as is known in the art.
  • the unit dosage parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.
  • intravenous or intraarterial infusion of a sterile aqueous solution including an active compound is an effective mode of administration.
  • Another embodiment is a sterile aqueous or oily solution or suspension including an active material injected as necessary to produce the desired pharmacological effect.
  • Injectables are designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to include a concentration of at least about 0.1 % w/w up to about 90% w/w or more, in some embodiments more than 1 % w/w, of the active compound to the treated tissue(s).
  • the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at intervals of time.
  • the precise dosage and duration of treatment is a function of the tissue being treated and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values also can vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of formulations provided herein.
  • the compounds can be formulated in any suitable vehicle or form.
  • they can be in micronized or other suitable form and/or can be derivatized to produce a more soluble active product or to produce a prodrug or for other purposes.
  • the form of the resulting mixture depends upon a number of factors, including, for example, an intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the condition and can be empirically determined.
  • a pharmaceutical composition is prepared for administration by injection wherein the pharmaceutical composition includes a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • injectable suspensions are prepared using appropriate liquid carriers and/or suspending agents.
  • Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampules or in multi dose containers.
  • Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and can include formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions can include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions also can include suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the pharmaceutical composition is prepared for administration by inhalation.
  • Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical compositions include a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator can be formulated.
  • Certain of such formulations include a powder mixture of a compound provided herein and a suitable powder base such as lactose or starch.
  • the pharmaceutical compositions provided are administered by continuous intravenous infusion. In certain of such embodiments, from 0.01 ⁇ g to 500 mg of the composition is administered per day. 3. Lyophilized powders
  • lyophilized powders which can be reconstituted for administration as solutions, emulsions and other mixtures. They also can be reconstituted and formulated as solids or gels.
  • the sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent.
  • the solvent can include an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that can be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent.
  • the solvent also can include a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, typically, about neutral pH.
  • each vial includes a single dosage of from 10 ⁇ g to 1000 mg. In another embodiment, each vial includes a single dosage of from 100 ⁇ g to 500 mg. In another embodiment, each vial includes a single dosage of from 0.1 mg to 50 mg. In another embodiment, each vial includes a single dosage of from 0.5 mg to 20 mg. In another embodiment, each vial includes a single dosage of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg. In another embodiment, each vial includes multiple dosages of the compound.
  • the lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.
  • Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration.
  • about 1 mg to 50 mg is added per mL of sterile water or other suitable carrier.
  • 5 mg to 35 mg is added per mL of sterile water or other suitable carrier.
  • 10 mg to 30 mg of lyophilized powder is added per mL of sterile water or other suitable carrier.
  • the precise amount depends upon the selected compound. Such amount can be empirically determined. 4.
  • Topical administration Topical mixtures are prepared as described for the local and systemic administration.
  • the resulting mixture can be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • Transdermal skin patches useful for administering the compounds disclosed herein include those well known to those of ordinary skill in that art.
  • the compounds or pharmaceutically acceptable derivatives thereof can be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma).
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will typically have diameters of less than 50 microns, in some embodiments less than 10 microns.
  • the pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical compositions include a propellant, e.g., dichlorodifluoro- methane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator can be formulated.
  • Certain of such formulations include a powder mixture of a compound provided herein and a suitable powder base such as lactose or starch.
  • compositions for nasal aerosol or inhalation administration include solutions that can include, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • the compounds can be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
  • Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.
  • Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients also can be administered. These solutions, particularly those intended for ophthalmic use, can be formulated as 0.01 % - 10% isotonic solutions, pH about 5-7, with appropriate salts.
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound provided herein.
  • the pharmaceutical composition is prepared for topical administration.
  • Certain of such pharmaceutical compositions include bland moisturizing bases, such as ointments or creams.
  • Any of the ointment bases known in the art including water in oil emulsion bases, oil in water emulsion bases, absorption bases, oleaginous bases and water soluble or water miscible bases can be used (e.g. , see Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995) at pages 1399-1404).
  • Oleaginous ointment bases are generally anhydrous and include, for example, vegetable oils, animal fats, and semisolid petroleum-based hydrocarbons.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, stearic acid and polyethylene glycols of varying molecular weight.
  • Creams are viscous liquids or semi-solid emulsions, and can be either oil-in-water or water-in-oil emulsions.
  • Cream bases are water- washable, and contain an oil phase, an emulsifier, and an aqueous phase, which can include a fatty alcohol.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant.
  • Lotions are preparations to be applied to the skin surface without friction, and often include a water or alcohol base, and include an emulsion and often solid particles (such as cocoa butter or fatty acid alcohols).
  • Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin.
  • Cream bases such as those including an emulsion of water, a mineral oil or petrolatum, one or more fatty alcohols or fatty esters, a polyoxyethylene ether or ester surfactant or polysorbate surfactant, also can be used.
  • Exemplary suitable cream bases include, but are not limited to, cold cream (USP), hydrous lanolin and hydrophilic ointment (USP).
  • the moisturizing bases can further contain various other emollients, emulsifiers, perfumes, colorants and preservatives.
  • Suitable water-in-oil emulsions are commercially available, e.g., blends of petrolatum, mineral oil, ceresin, lanolin alcohol, panthenol, glycerin and bisabolol under the designation AquaphorTM, available from Beiersdorf Futuro Inc.
  • Suitable oil-in- water emulsions are commercially available, e.g., water, mineral oil, petrolatum; sorbitol, stearic acid, lanolin, lanolin alcohol, cetyl alcohol, glyceryl stearate/ PEG-100 stearate, triethanolamine, dimethicone, propylene glycol, microcrystalline wax, tri(PPG-3 myristyl ether) citrate, disodium EDTA, methylparaben, ethylparaben, propylparaben, xanthan gum, butylparaben and methyldibromo glutaronitrile, such as LubridermTM Cream, available from Pfizer (Morris Plains, NJ); a blend of purified water, petrolatum, mineral oil, cetostearyl alcohol, propylene glycol, sodium laurel sulfate, isopropyl palmitate, imidazolidinyl urea, methylparaben
  • the formulation, route of administration and dosage for the pharmaceutical composition provided herein can be chosen in view of a particular subject's condition (see e.g., Fingl et al., "The Pharmacological Basis of Therapeutics", Chapter 1 , p. 1 (1975)).
  • the pharmaceutical composition is administered as a single dose.
  • a pharmaceutical composition is administered as a series of two or more doses administered over one or more days.
  • compositions for other routes of administration are provided.
  • the pharmaceutical composition is prepared for topical administration such as rectal administration.
  • the pharmaceutical dosage forms for rectal administration include, but are not limited to rectal suppositories, capsules and tablets for systemic effect.
  • a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema.
  • Certain of such pharmaceutical agents include known ingredients, such as cocoa butter and/or other glycerides.
  • Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
  • bases examples include cocoa butter (theobroma oil), glycerin-gelatin, Carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases can be used.
  • the pharmaceutical compositions include moisturizing bases, such as ointments or creams. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substances and by the same methods as for formulations for oral administration. F. Articles of manufacture
  • the compounds provided herein or pharmaceutically acceptable derivatives or prodrugs, or pharmaceutical compositions that include such compounds can be packaged as articles of manufacture including packaging material, within the packaging material a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for modulating the activity of androgen receptor, or for treatment, prevention or amelioration of one or more symptoms of androgen receptor mediated diseases or disorders, or diseases or disorders in which androgen receptor activity is implicated, and a label that indicates that the compound or composition is used for modulating the activity of androgen receptor or for treatment, prevention or amelioration of one or more symptoms of androgen receptor mediated diseases or disorders, or diseases or disorders in which androgen receptor activity is implicated.
  • the articles of manufacture provided herein include packaging materials.
  • Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252.
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • a wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder in which androgen receptor activity is implicated as a mediator or contributor to the symptoms or cause.
  • the pharmaceutical compositions can be presented in a pack or dispenser device which can include one or more unit dosage forms including a compound provided herein.
  • the pack can for example include metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be accompanied by instructions for administration.
  • the pack or dispenser also can be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, can be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions including a compound provided herein formulated in a compatible pharmaceutical carrier also can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Kits can include a pharmaceutical composition described herein and an item for administration.
  • a selective androgen receptor modulator provided herein can be supplied with a device for administration, such as a syringe, an inhaler, a dosage cup, a dropper, or an applicator.
  • the kit can, optionally, include instructions for application including dosages, dosing regimens and instructions for modes of administration.
  • Kits also can include a pharmaceutical composition described herein and an item for diagnosis. For example, such kits can include an item for measuring the concentration, amount or activity of androgen receptor of a subject. H. Evaluation of the activity of the compounds
  • Standard physiological, pharmacological and biochemical procedures are available for testing the compounds provided herein to identify those that possess activity as selective androgen receptor modulators.
  • In vitro and in vivo assays known in the art can be used to evaluate the activity of the compounds provided herein as selective androgen receptor modulators.
  • Exemplary assays include, but are not limited to, fluorescence polarization assay, luciferase assay and co-transfection assay.
  • SARMs can be identified using a series of in vitro cell-assays that profiles ligand mediated activation of AR (e.g., see U.S. Pat. No. 7,196,076).
  • AR agonistic activity can be determined by monitoring the ability of the SARM compounds to maintain and/or stimulate the growth of AR-containing tissue such as prostate and seminal vesicles, as measured by weight.
  • AR antagonistic activity can be determined by monitoring the ability of the SARM compounds to inhibit the growth of AR-containing tissue.
  • the agonist and antagonist effects of SARMs can be measured in non-tumor tissues via a series of in vivo rat models in which surrogate endpoints are measured in tissues including, but not limited to, the prostate, seminal vesicle, and levitor ani muscle, as well as the hypothalamic axis via measurement of plasma luteinizing hormone (LH) levels.
  • LH plasma luteinizing hormone
  • the Sprague-Dawley rat model has been used extensively as a model for identifying selective androgen receptor modulators (SARMs) with in vivo pharmacological activity, thereby identifying active, non-steroidal selective androgen receptor modulators that can be useful therapeutics, such as for enhancing muscle, bone, and sexual function and treating prostate cancer (e.g., see Yin et al., J Pharmacol Exp Ther 304(3): 1334-1340 (2003), Jasuja et al., Endocrinology 146(10): 4472 ⁇ 4478 (2005), Miner et al., Endocrinology 148(1): 363-373 (2007), Morrissey et al., Journal of Andrology 23(3): 341-351 (2002), Adesanya et al., Scientific Research and Essay 2(8): 309-314 (2007).
  • SARMs selective androgen receptor modulators
  • the agonist or antagonist activity of a potential SARM also can be measured in a normal, non-tumor cell line.
  • normal, non-tumor cells lines include, but are not limited to, primary rat prostate epithelial and stromal cells, murine muscle cell line C2C12, primary guinea pig smooth muscle cells, primary smooth-muscle cells from immature (I-PSMC) or adult (A-PSMC) rat penis, primary rabbit smooth muscle cell line, prostatic smooth muscle cell line PS-I , prostatic smooth muscle cell line PSMCl , mouse bone cell cultures and osteoblasts cells and primary rat seminal vesicle lines SVC-I and SCV-2 (e.g., see Chen et al, FEBS Letters 491 : 91-93 (2001), Gerdes et al., Endocrinology 139: 3569-3577 (1998), Gonzalez-Cadavid et al, MoI.
  • surrogate endpoint in vivo assays also can be used to examine the effects of a potential SARM on the AR pathway. These assays measure the effects of a potential SARM on normal androgen dependent tissues and functions, such as, but not limited to, prostate, seminal vesicle, levator ani muscle, bone, libido, fertility and hypothalamus (measurement of blood LH levels). These assays are widely recognized as having a direct correlation to the effects of a potential SARM on the AR pathways in humans. Exemplary surrogate endpoint in vivo assays are described in Ashby et al, J. Appl. Tox.
  • Animal models bearing a hormone-dependent tumor also can be used to assess the antagonist activity of a potential SARM against the tumor and the agonist or antagonist activity against AR-containing normal non-tumor tissues in the animal.
  • the above surrogate endpoint in vivo assays can be run using a rat bearing an androgen-dependent rat prostate tumor, such as Dunning R-3327.
  • effects of a SARM on a rat androgen-dependent prostate tumor can be determined while simultaneously examining the effects of the SARM agent on AR- containing normal non-tumor tissues such as, but not limited to, prostate, seminal vesicle, and levitor ani muscle as well as effects on the hypothalamic axis via measurements of plasma LH levels.
  • immune compromised nude rats bearing human androgen-dependent prostate tumors can be used.
  • effects of a SARM on a human androgen-dependent prostate tumor can be determined while simultaneously examining the effects of the SARM agent on normal tissues such as, but not limited to, prostate, seminal vesicle, and levitor ani muscle as well as effects on the hypothalamic axis via measurements of plasma LH levels.
  • in vivo rat assays can be used to determine the effect of SARMs on libido and reproduction.
  • the compounds provided herein are capable of modulating activity of androgen receptor in a "co-transfection” assay (also called a “cis-trans” assay), which is known in the art (see e.g., Evans et al., Science 240: 889- 95 (1988); U.S. Patent Nos. 4,981,784 and 5,071,773; and Pathirana et al., "Nonsteroidal Human Progesterone Receptor Modulators from the Marie Alga Cymopolia Barbata," MoI. Pharm. 47: 630-35 (1995)). Modulating activity in a co- transfection assay has been shown to correlate with in vivo modulating activity.
  • such assays are predictive of in vivo activity (see, e.g., Berger et al., J. Steroid Biochem. Molec. Biol. 41 : 773 (1992)).
  • the in vitro biology of the compounds provided herein can be determined using any assay known in the art.
  • the co-transfection assay as described herein or in the art, can be used.
  • the co-transfection assay provides functional activity expressed as agonist EC 50 and antagonist IC 50 values.
  • two different co-transfection plasmids are prepared.
  • cloned cDNA encoding an intracellular receptor e.g., androgen receptor
  • a constitutive promoter e.g., the SV 40 promoter
  • cDNA encoding a reporter protein such as firefly luciferase (LUC)
  • LEC firefly luciferase
  • Expression of the first co-transfection plasmid results in production of the intracellular receptor protein.
  • Activation of that intracellular receptor protein results in production of a receptor-dependant activation factor for the promoter of the second co-transfection plasmid.
  • That receptor-dependant activation factor in turn results in expression of the -I l l- reporter protein encoded on the second co-transfection plasmid.
  • reporter protein expression is linked to activation of the receptor.
  • that reporter activity can be conveniently measured (e.g., as increased luciferase production).
  • co-transfection assays can be used to identify agonists, partial agonists, and/or antagonists of intracellular receptors.
  • to identify agonists co-transfected cells are exposed to a test compound. If the test compound is an agonist or partial agonist, reporter activity is expected to increase compared to co-transfected cells in the absence of the test compound.
  • to identify antagonists the cells are exposed to a known agonist (e.g., androgen for the androgen receptor) in the presence and absence of a test compound. If the test compound is an antagonist, reporter activity is expected to decrease relative to that of cells exposed only to the known agonist.
  • An exemplary co-transfection assay is the luciferase reporter assay (Evans, Science 240: 889-895 (1988), Berger et al, J Steroid Biochem MoI Biol 41 : 733-738 (1992)) can be used to establish the ability of a compound of formulae I, II or III to activate (agonist activity) or repress (antagonist activity) the ability of the human androgen receptor (hAR) to induce gene expression.
  • a human cell line containing endogenously expressed hAR (e.g., MDA-MB-453 cells, derived from a human mammary carcinoma, American Tissue Type Culture Collection [ATCC] HTB 131) can be transfected with an androgen responsive luciferase reporter plasmid to measure the level of cross-reactivity of the compound on other nuclear receptors (such as the glucocorticoid receptor (GR), estrogen receptor (ER), mineralocorticoid receptor (MR), progesterone receptor (PR), retinoid receptor (RAR), retinoid X receptor (RXR), peroxisome proliferator activating receptors alpha (PPAR ⁇ ), gamma (PPAR ⁇ ) and delta (PPAR ⁇ ), liver X receptor (LXR), farnesyl X receptor (FXR) and the pregnane X receptor (PXR)).
  • GR glucocorticoid receptor
  • ER estrogen receptor
  • MR mineralocorticoid receptor
  • luciferase reporter plasmids containing the cDNA for firefly luciferase (LUC) under the control of a conditional promoter containing hormone response elements recognized by the appropriate nuclear receptor are co-transfected into cells with the nuclear receptor expression plasmid.
  • LOC firefly luciferase
  • Any appropriate nuclear receptor expression plasmid known in the art can be used.
  • plasmids are the reporter plasmid MMTV-LUC, which contains the mouse mammary tumor virus (MTV) long terminal repeat (LTR), which is a conditional promoter containing hormone response elements recognized by AR, GR, MR and PR (Giguere et al, Cell 46: 645-652 (1986)).
  • MTV- ERE5-LUC contains the mouse MTV LTR in which the hormone response elements have been deleted and replaced with five copies of a 33-base pair estrogen response element (ERE) recognized by ER (McDonnell et al, J Biol Chem 269: 1 1945-1 1949 (1994)).
  • the reporter plasmid MTV-TREp-LUC contains two copies of a thyroid hormone response element (TRE) sequence, recognized by RAR (Bissommette et al, MoI Cell Biol 15(10): 5576-5585 (1995), Umesono et al, Nature 336(6196): 262-265 (1988)).
  • the reporter plasmid CRBP-(2)-tk-LUC contains two copies of a response element sequence from the cellular retinoid binding protein (CRBP) promoter, recognized by RXR, linked to the tk promoter (Mangelsdorf et al, Cell 66(3): 555- 561 (1991)).
  • the promoter plasmid pPREA3-tk-LUC contains a response element sequence from the acyl CoA oxidase gene, recognized by PPAR ⁇ , linked to the tk promoter (Kliewer et al, Nature 355(6359): 446-449 (1992)).
  • the reporter plasmid LXRE-tk-LUC contains a response element sequence recognized by LXR, linked to the tk promoter (Willy et al, Genes Dev 9(9): 1033-1045 (1995)).
  • the reporter plasmid EcRE7-tk-LUC contains a response element sequence recognized by FXR, linked to the tk promoter (Forman et al, Cell 81(5): 687-693 (1995)).
  • the reporter plasmid CYP3Al-tk-LUC contains a response element from the CYP3A1 promoter that is recognized by PRX, linked to the tk promoter.
  • receptor plasmid expression plasmid known in the art can be used in the assay.
  • exemplary receptor expression plasmids include pRShGR (Giguere et al, Cell 46: 645-652 (1986)), pRShMR (Arriza et al, Science 237: 268-275 (1987)), pSVhPR- B (Vegeto et al, Cell 69: 703-713 (1992)), pRShRXR ⁇ (Boehm et al, J Med Chem 37(18): 2930-2941 (1994)), pCMVhPPAR ⁇ (Willy et al, Genes Dev 9(9): 1033-1045 (1995)), pCMVGAL4hPPAR ⁇ , pCMVGAL4hPPAR ⁇ , pCMV-LXR ⁇ and pCMV- FXR ⁇ (Cesario et al, MoI Endocrinol 15(8): 1360-1369 (2001)).
  • the cotransfections are performed using known methods (Berger et al, J Steroid Biochem MoI Biol 41 : 733-738 (1992)).
  • PPAR ⁇ , LXR ⁇ , FXRo; and PXR ⁇ assays are transiently transfected into cells using a non-liposomal formulation (e.g., the FuGENE 6 transfection reagent, Roche, Indianapolis, IN, according to manufacturer's specifications).
  • a non-liposomal formulation e.g., the FuGENE 6 transfection reagent, Roche, Indianapolis, IN, according to manufacturer's specifications.
  • Tissue selective androgen receptor agonists provided herein typically have EC 50 values of 1 micromolar or less and efficacy values greater than about 50% in a standard AR assay, such as the co-transfection assay described herein.
  • the EC 50 is in the range of 1 to 1000 ⁇ M.
  • the EC 50 is in the range of 1 to 500 ⁇ M.
  • the EC 50 is in the range of 1 to 100 ⁇ M.
  • the EC 50 is less than 100 ⁇ M.
  • the EC 50 is less than 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 or 1 ⁇ M.
  • the efficacy values are greater than about or at 55%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125% or greater.
  • the compounds provided herein have an EC 50 value of 10 ⁇ M or less and an efficacy value greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.
  • the compounds provided herein have an EC 5O value of about or 1 ⁇ M to about or 5 ⁇ M and an efficacy value greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.
  • the compounds provided herein exhibit an EC 50 value of no greater than 10 micromolar, or no greater than 1 micromolar, or no greater than 100 nanomolar, or no greater than 10 nanomolar or no greater than 1 nanomolar in an assay for determination of AR receptor antagonist activity.
  • Tissue selective androgen receptor antagonists provided herein typically have IC 50 values of 1 micromolar or less and efficacy values greater than about or 50% in a standard AR assay, such as the co-transfection assay described herein.
  • the IC 50 is in the range of 1 to 1000 ⁇ M.
  • the IC 50 is in the range of 1 to 500 ⁇ M.
  • the IC 50 is in the range of 1 to 100 ⁇ M.
  • the IC 50 is less than 100 ⁇ M.
  • the IC 50 is less than 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 or 1 ⁇ M.
  • the efficacy values are greater than about or at 55%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 1 10%, 1 15%, 120%, 125% or greater.
  • the compounds provided herein have an IC 5 O value of 10 ⁇ M or less and an efficacy value greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.
  • the compounds provided herein have an IC 50 value of about or at 1 ⁇ M to about or at 5 ⁇ M and an efficacy value greater about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.
  • the compounds provided herein exhibit an IC 50 value of no greater than 10 micromolar, or no greater than 1 micromolar, or no greater than 100 nanomolar, or no greater than 10 nanomolar or no greater than 1 nanomolar in an assay for determination of AR receptor antagonist activity.
  • the compounds provided herein exert their receptor-modulatory effects with high selectivity. This means that they do not bind to certain other receptors (other than AR receptors) with high affinity, but rather only bind to, activate, or inhibit the activity of other receptors with affinity constants of greater than 1 micromolar ( ⁇ M). In some embodiments, the compounds only bind to, activate, or inhibit the activity of other receptors with affinity constants of greater than 100 ⁇ M. In some embodiments, the compounds only bind to, activate, or inhibit the activity of other receptors with affinity constants of greater than 1000 ⁇ M.
  • the high selectivity of the compounds provided herein can reduce the incidence of side effects caused by undesirable activation or antagonism of other one or more other receptor(s).
  • the compounds provided herein activate AR-induced gene expression. This was demonstrated in the cotransfection assay in MDA-MB-453 cells. In assays measuring the affinity and functional activation of AR by compounds provided herein, compounds of formula I activated AR-dependent gene expression. For example, Compound 102 demonstrated consistently higher potency than other tested androgen modulator compounds in binding to AR protein, in activating AR in a functional assay, in stimulating expression of a key gene in muscle cells, and in repressing a key inflammatory modulator in bone cells.
  • Skeletal ⁇ -actin is a major component of skeletal muscle. Androgens play a role in increasing muscle mass and strength (Mooradian et al, Endocr Rev 8: 1-28 (1987); Bhasin et al, J Clin Endocrinol Metab 82: 407-413 (1997); and Bhasin et al, N Engl J Med 335: 1-7 (1996)). Androgens up-regulate oactin mRNA in rat levator ani skeletal muscle and hence AR-mediated modulation of skeletal ⁇ -actin promoter activity is a marker for studying androgen regulation of gene expression in muscle. The effect the compounds provided herein on muscle can be tested by any method known in the art.
  • MHC myosin heavy chain
  • mRNA expression parallels the pattern of MHC protein expression. Because transcription of MHC mRNA occurs in advance of MHC protein translation, and the increased sensitivity of RT-PCR compared to western blotting, rapid changes in mRNA expression can be detected and used to analyze the subtle dynamic effects on muscle metabolism. An anabolic effect on masseter muscle is demonstrated increasing transcription of MHC, such as MHC type as compared to the untreated control.
  • An exemplary assay for measuring AR-mediated gene expression in mouse muscle cells is the human skeletal oactin assay.
  • a mouse muscle cell line (C2C12, obtained from American Type Cell Culture (ATCC, Rockville, MD)) can be used in the luciferase reporter assay.
  • An SK oactin-LUC reporter plasmid is constructed by inserting the skeletal Qf-actin promoter sequence into a luciferase reporter vector ⁇ e.g., by cloning the human skeletal ⁇ -actin promoter region from -77 to +202 bp from human liver genomic DNA (Clontech, Palo Alti, CA) and inserting the sequence into a pGL3-Basic reporter plasmid (Promega, Madison, WI)).
  • the C2C12 cell line can be transiently transfected with a human AR expression plasmid and a luciferase reporter plasmid containing the skeletal ⁇ -actin promoter upstream of the luciferase cDNA.
  • the compounds to be tested are added to the cells after transfection and after 24 hours of incubation, the cells are lysed with a detergent-containing buffer and assayed for luciferase activity.
  • the EC 50 is determined from the concentration response curve for the compound, and efficacy is calculated by comparison with the standard androgen agonist, dihydrotestosterone.
  • Anabolic activity of the compounds provided herein on bone can be tested by any method known in the art. Such methods include bone formation rate, which can be assessed by osteocalcin level measurement. Plasma osteocalcin levels can be determined using any method known in the art (e.g., see Koyama et al, J Immunol Methods 139(1): 17-23 (1991)). A commercially available rat osteocalcin EIA kit is available from Biomedical Technologies Inc. (Stoughton, MA).
  • Additional assays include bone nodule formation assays (Vanderschueren et al, Endocrine Reviews 25(3): 389-425 (2004), Beresford et al, 45(2): 163-178 (2005) and use of rodent models of osteoporosis (e.g., see Gowen et al, J Clin Invest. 105 : 1595-604 (2000); Pietschmann et al, Exp Gerontol. 42(11): 1099-1 108 (2007); and Wang et al, Bone. 29(2): 141-148 (2001)). Bone turnover markers also have been demonstrated to be an effective, validated tool for monitoring bone activity.
  • bone alkaline phosphatase, urinary hydroxyproline, serum alkaline phosphatase, tartrate-resistant acid phosphatase, osteocalcin levels, and urinary calcium-creatinine ratio are used as bone turnover markers (e.g., Sit et al, Adv Ther. 24(5): 987-995 (2007); Szulc et al, Osteoporos Int. 18(1 1): 1451-61 (2007); and Harmon et al, Cancer Treat Rev. 32 Suppl 1 : 7-14 (2006)).
  • C-telopeptide is used as a bone resorption marker (e.g., see Srivastava et al, Calcified Tissue International 66(6): 435-442 (2000)).
  • IL-6 is an important bone resorption factor (Jilka et al, Science 257: 88-91 (1992); Bellido et al, J Clin Invest 95: 2886-2895 (1995)). Overexpression of IL-6 can cause severe bone loss in vivo. In vitro studies have indicated that cytokines, such as TNF ⁇ and IL- 1/3 strongly stimulate IL-production through the induction of NF K B (Kurokouchi et al, J Bone Mineral Res 13: 1290-1299 (1998); Ng et al, J Biol Chem 269: 19021-19027 (1994)).
  • the assay is a cotransfection assay that measures the ability of compound to repress gene expression via the human androgen receptor from the IL-6 promoter using a luciferase reporter assay in human osteoblast cells.
  • a human osteoblast cell line (Saos-2, available from American Type Cell
  • An IL- 6-LUC reporter plasmid can be constructed by inserting the IL-6 promoter sequence into a luciferase reporter vector (e.g. , by cloning the human IL-6 promoter region from -232 to +17 bp from human liver genomic DNA (Clontech, Palo Alti, CA) and inserting the sequence into a pGL2-enhancer reporter plasmid (Promega, Madison,
  • the Saos-2 cell line can be transiently transfected with a human AR expression plasmid and a luciferase reporter plasmid containing the IL-6 promoter upstream of the luciferase cDNA.
  • the compounds to be tested are added to the cells after transfection and after 24 hours of incubation, the cells are lysed with a detergent- containing buffer and assayed for luciferase activity.
  • the EC 5O is determined from the concentration response curve for the compound, and the inhibitory effect on TNFo/IL-l ⁇ induction (% inhibition) can be calculated according to the equation:
  • %Inhibition F(TNFoZIL- Iff control - basal) - (androgen treatment - basal)] x J QQ
  • 3 control - basal mean luciferase response measured in cells treated with media containing TNF ⁇ and IL-I ⁇ without test compound
  • basal mean luciferase response measured in cells treated with media alone
  • androgen treatment mean luciferase response measured in cells treated with media containing TNF ⁇ and IL-I ⁇ with test compound.
  • Antagonist Activity Against Hormone-Dependent Tumors Various methods for identifying SARMs having antagonist activity against hormone-dependent tumors while exhibiting no activity, or agonist activity against other non-tumor tissues containing the androgen receptor, can be used. For example, antagonist activity in hormone-dependent tumors can be ascertained by screening the compounds in hormone-dependent tumor cell lines for inhibition of growth, either in vitro or in vivo.
  • hormone-dependent tumor cell lines that can be used for screening potential SARMs include, but are not limited to, human breast tumor cell line MDA MB453, human breast tumor cell line ZR-75-1, murine breast line Shionogi, rat prostate adenocarcinoma line Dunning R-3327, human prostate tumor cell line MDA PCa 2a and PCa 2b, human prostate cell line LNCap, human prostate tumor cell line CWR22, human prostate tumor cell line LuCaP 35 and LuCaP 23.12, human prostate cell line LAPC-4 and LAPC-9, human prostate tumor cell line PC- 295, human prostate tumor cell line PC-310, and human osteosarcoma cell line MG- 63.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a bacterial or mammalian, including human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • a cell line such as a bacterial or mammalian, including human, cell line.
  • the results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • Exemplary assays include bacterial reverse mutation assays (e.g, see Ames et al., Mutation Research 31 : 347-364 (1975); Green et al, Mutation Research 38: 3-32 (1976); and Maron et al, Mutation Research 113: 173-215 (1983), cytological methods for detecting chemical mutagens (Evans, Chemical Mutagens, Principles and Methods for their Detection, Vol.
  • the toxicity of particular compounds in an animal model may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • Non- limiting examples of appropriate in vivo animal models include castrated male rats or aged male orchidectomized rats.
  • human clinical trials also can be used to determine the efficacy of a compound in humans. 5.
  • baculovirus expression plasmid including cDNA encoding the human steroidal hormone receptor protein (AR, PR, GR, MR, or ER) can be prepared using standard techniques. See e.g., Allegretto et al, J. Biol. Chem. 268: 26625 (1993); Srinivasan and Thompson, MoI. Endo. 4: 209 (1990); and D. R. O'Reilly et al, in "Baculovirus Expression Vectors", D. R. O'Reilly et al, eds., W. H. Freeman, New York, N. Y., pp.
  • the expression plasmid is infected together with wild type Autographa californica multiple nuclear polyhedrosis virus DNA into Spodopter frugiperda-2 ⁇ (Sf-21) cells to generate recombinant virus including AR cDNA.
  • Sf-21 Spodopter frugiperda-2 ⁇
  • the recombinant virus then can be used to infect cells, such as Sf-21 cells.
  • the infected Sf-21 cells are incubated for 48 hours and then collected by centrifugation, resuspended in lysis buffer (50 mM potassium phosphate buffer, pH 7.0, 10 mM monothioglycerol, 5 mM DTT, 20 mM sodium molybdate, 1 mM PMSF, 1 ⁇ g/mL aprotinin, and 10 ⁇ g/mL leupeptin) and homogenized.
  • lysis buffer 50 mM potassium phosphate buffer, pH 7.0, 10 mM monothioglycerol, 5 mM DTT, 20 mM sodium molybdate, 1 mM PMSF, 1 ⁇ g/mL aprotinin, and 10 ⁇ g/mL leupeptin
  • Binding assay samples can be prepared in separate mini-tubes in a 96-well format using Receptor- Assay Buffer (10% glycerol, 25 mM sodium phosphate, 10 mM potassium fluoride, 10 mM sodium molybdate, 0.25 mM CHAPS, 2 mM DTT and 1 mM EDTA, (adjusted to pH 7.5)) containing 50 ⁇ g of receptor lysate; 2-4 nM of [ 3 H] -steroid (dihydrotestosterone, progesterone, dexamethasone, aldosterone, or estradiol) at 50-100 Ci/mmol; and either a reference compound or a test compound.
  • Receptor- Assay Buffer 10% glycerol, 25 mM sodium phosphate, 10 mM potassium fluoride, 10 mM sodium molybdate, 0.25 mM CHAPS, 2 mM DTT and 1 mM EDTA,
  • Test compounds included selective androgen receptor binding compounds as provided herein.
  • Reference compounds were unlabeled steroids, which have been previously shown to bind to the steroid hormone receptors, such as dihydrotestosterone for androgen receptors.
  • Each reference compound and test compound are assayed at varying concentrations, e.g., ranging from 3.2 x 10 "10 to 10 "5 M and the assay samples are incubated, e.g., for 16-24 hours at 4°C.
  • Average Non-specific CPM is the amount of radioactivity from samples including an excess ⁇ e.g., 1000 nM) of unlabeled steroid, such as dihydrotestosterone.
  • IC 50 values (the concentration of test compound required to decrease specific binding by 50%) were determined using the log-logit (Hill) method.
  • the compounds provided herein exhibit a Kj of no greater than 10 micromolar, or no greater than 5 micromolar, or no greater than 1 micromolar, or no greater than 100 nanomolar, or no greater than 10 nanomolar or no greater than 1 nanomolar in an AR receptor binding assay. 6.
  • the Sprague-Dawley rat model is used in the art as a model for identifying selective androgen receptor modulators (SARMs) that exhibit in vivo pharmacological activity, thereby identifying active, nonsteroidal selective androgen receptor modulators.
  • SARMs selective androgen receptor modulators
  • the effects of androgens in skeletal muscle can be assessed by monitoring the weight of the levator ani muscle (Herschberger et al, Proc Soc Exp Biol Med 83: 175-180 (1981)), a muscle that expresses high levels of androgen receptor (Max et al, Biochem J 200: 77-82 (1981)).
  • Androgens also stimulate sebaceous gland secretions in the skin and have been linked with increased sebum production and acne (Boudou et al, J Clin Endocrinol Metab 80(4): 1158-1161 (1995)).
  • the preputial gland in rodents is a modified sebaceous gland and has been used as an indicator of sebum production (Miyake et al., J Invest Dermatol 103: 721-725 (1994); Nickerson et al, Acta Anat (Basel) 94: 481-489 (1976); and Deplewski et al., Endocrinology 138: 4416-4420 (1997)). Androgen supplementation increases the weight of sebaceous glands and their secretions.
  • Osteopenia is a degenerative process that can be reversed with testosterone supplementation (Finkelstein et al, J Clin Endocrinol & Metabolism 69: 776-783 (1989); Behre et al, J Clin Endocrinol & Metabolism 82: 2386-2390 (1997); and Katznelson et al, J Clin Endocrinol & Metabolism 81 : 4358- 4365 (1996)).
  • a similar phenomenon can be observed in male rats in which bone loss due to castration can be restored by administering androgen (Wakley et al, J Bone & Mineral Research 6: 325-330 (1991)).
  • biochemical markers such as serum osteocalcin
  • Osteocalcin is a bone matrix protein component that is synthesized and deposited by bone-forming osteoblasts and it is also released from the bone during bone resorption by osteoclasts (Ivaska et al, J Biol Chem 279: 18361-18369 (2004)). During both processes, this protein and its breakdown products are released into the circulation and can served as biochemical markers.
  • Measurement of circulating osteocalcin levels in the serum of rats can by used to assess bone turnover or metabolism (Vanderschueren et al, Endocrinology 141(5): 1642-1647 (2000); Vanderschueren et al, Bone Miner 26(2): 123-131 (1994); and Hunter et al, Arthritis Res Ther 10(4): R102 (2008)).
  • Mature male Sprague-Dawley rats of approximately 2 months of age generally are used. After a one-week acclimation period, they are castrated under isoflurane anesthesia. One group of animals is sham-operated and treated with vehicle and serves as a control. After surgery, the rats are sorted into groups so that no statistically significant differences in body weight are observed. Treatment generally begins the same day of the surgery after the surgical procedure. Animals are treated either orally (4 mlVkg) or subcutaneously (0.4 mL/kg) each morning for 14 consecutive days with vehicle or various compound solutions of different strengths. Approximately 24 hours after the last dose, rats are sacrificed by decapitation and organs and blood collected.
  • Trunk blood is collected and then the ventral prostate, seminal vesicles and levator ani muscle are dissected out, blotted dry and weighed individually.
  • the blood is allowed to clot at room temperature and the serum separated by centrifugation.
  • the serum is then collected and kept frozen until processed for measurement of LH levels by radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • Serum samples are assayed for LH with a double antiserum procedure using reagents from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
  • samples and standards (NIDDK-rLH-RP-3) in a total volume of 200 ⁇ l are incubated at room temperature for 2-3 days with 100 ⁇ l primary antiserum (rabbit NIDDK-anti-rLH-S-1 1) diluted 1 : 100,000. Thereafter, 100 ⁇ l of iodinated LH (Covance Laboratories Inc.) diluted to 200,000-300,000 cpm/ml is added to the tubes and incubation continued for an additional 24 hour period.
  • Bound hormone is separated from free hormone by precipitation with a specific goat anti-rabbit serum (GARS; Antibodies Inc). For this purpose, 50 ⁇ l of 4% normal rabbit serum is added to each incubation tube, after which an additional 50 ⁇ l of a 1 : 10 GARS solution is added. The tubes are vortexed and incubated overnight at 4 0 C. The assay is terminated by centrifugation at 2,500 rpm for 30 min in a centrifuge at 4 0 C. The supernatants are decanted and discarded and the pellets are counted in a 10-channel gamma-counter. The assay has a minimal detectable amount of 0.001 ng/tube and the intra- and inter-assay variability is less than 10%. In order to minimize interassay variability, all samples from a single study are run in the same assay.
  • GAS goat anti-rabbit serum
  • Results are analyzed by analysis of variance on Box-Cox transformed data (Box and Cox, J Roy Statist Soc Series B 26: 211-252 (1964), Box and Hill, Technometrics 16: 385-389 (1974) and Peltier et al, J. Anim. Sci. 76: 847-849 (1998)).
  • Box-Cox transformed data Box-Cox transformed data
  • the logarithm of the data are used for statistical analysis.
  • Seminal vesicle and levator ani muscle data are elevated to 0.2 and 0.6, respectively.
  • a P ⁇ 0.05 is considered as the minimum criterion to declare statistically significant differences.
  • efficacy data are calculated as percentage of the response observed in the sham-operated group.
  • the orchidectomized, vehicle- treated group is considered as 0% efficacy, whereas the sham-operated group represented 100% efficacy. This conversion allows direct comparison of data independently of having different controls as is the case in experiments using subcutaneously and orally administered compounds.
  • Potencies are estimated on the transformed data using a four-parameter logistic equation.
  • the model estimates EC 50 's in a logarithmic scale, since log EC 50 is a more robust estimate of the potency (Ghosh et ah, J Biopharm Stat 8: 645-665 (1998)).
  • the model also provides a SE for the estimate that is used to calculate 95% confidence limits of the estimated potencies.
  • the following equation exemplifies the basic, reparametrized four parameter logistic equation used in estimating potencies in these studies:
  • a - D + D where A is the maximum, D is the minimum, B is the slope, C is either the EC 50 or the IC 50 depending on the direction of the response, and x is the dose of the compound used.
  • Methods of use of the compounds and compositions provided herein also are provided.
  • the methods include in vitro and in vivo uses of the compounds and compositions for altering androgen receptor activity and for treatment, prevention, or amelioration of one or more symptoms of diseases or disorder that are modulated through androgen receptor activity, or in which androgen receptor activity is implicated.
  • provided herein are methods of treating a subject by administering a compound provided herein.
  • such subject exhibits symptoms or signs of a androgen receptor mediated condition.
  • a subject is treated prophylactically to reduce or prevent the occurrence of a condition.
  • a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof can be used to treat a condition including, but not limited to, maintenance of muscle strength and function ⁇ e.g., in the elderly); reversal or prevention of frailty or age-related functional decline ("ARFD") in the elderly ⁇ e.g., sarcopenia); treatment of catabolic side effects of glucocorticoids; prevention and/or treatment of reduced bone mass, density or growth ⁇ e.g., osteoporosis and osteopenia); treatment of chronic fatigue syndrome (CFS); chronic myalgia; treatment of acute fatigue syndrome and muscle loss following elective surgery (e.g.
  • AFD frailty or age-related functional decline
  • CFS chronic fatigue syndrome
  • chronic myalgia treatment of acute fatigue syndrome and muscle loss following elective surgery
  • post-surgical rehabilitation accelerating of wound healing; accelerating bone fracture repair (such as accelerating the recovery of hip fracture patients); accelerating healing of complicated fractures, e.g. distraction osteogenesis; in joint replacement; prevention of post-surgical adhesion formation; acceleration of tooth repair or growth; maintenance of sensory function (e.g., hearing, sight, olfaction and taste); treatment of periodontal disease; treatment of wasting secondary to fractures and wasting in connection with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic state (e.g., coma), eating disorders (e.g., anorexia) and chemotherapy; treatment of cardiomyopathy; treatment of thrombocytopenia; treatment of growth retardation in connection with Crohn's disease; treatment of short bowel syndrome; treatment of irritable bowel syndrome; treatment of inflammatory bowel disease; treatment of Crohn's disease and ulcerative colitis; treatment of complications associated with transplantation; treatment of physiological short stature including
  • Exemplary conditions that can be treated with the selective androgen receptor modulators provided herein include, but are not limited to, hypogonadism, wasting diseases, cancer cachexia, frailty, infertility, osteoporosis, hirsutism, acne, male-pattern baldness, prostatic hyperplasia, and cancer, including, but not limited to, various hormone-dependent cancers, including, without limitation, prostate and breast cancer.
  • a selective androgen receptor agonist or partial agonist is used for male hormone replacement therapy.
  • one or more selective androgen receptor agonists and/or partial agonists are used to stimulate hematopoiesis.
  • a selective androgen receptor agonist or partial agonist is used as an anabolic agent.
  • a selective androgen receptor agonist and/or partial agonist is used to improve athletic performance.
  • a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is administered to a subject in order to treat a condition responsive to an AR modulator compound.
  • the method includes administering to a subject having a condition responsive to an AR modulator compound a therapeutically effective amount of one or more than one compound provided herein to treat the condition responsive to an AR modulator compound.
  • the condition is treated by agonizing the androgen receptor.
  • the condition is treated by antagonizing the androgen receptor.
  • the condition treated is selected from among hypogonadism, lower than normal testosterone plasma levels, infertility, sexual arousal disorder, disorders of libido, muscle wasting, cachexia, sarcopenia, frailty, bone density loss, mood disorders (including lack of well being, lack of vigor, anger, irritability, sadness, tiredness, nervousness and depression), impaired cognitive function (including verbal fluency and spatial memory), neurodegenerative disorders, including Alzheimer's disease, mild cognition impairment, Lewis body dementia, and frontal temporal dementia, xerophthalmia, metabolic disorders, including dyslipidemia, atherosclerosis, and non-insulin dependent diabetes (NIDDM), cardiovascular disorders including but not limited to hypertension, coronary artery disease, and myocardial perfusion, obesity, anemia, prostate cancer, and schizophrenia.
  • NIDDM non-insulin dependent diabetes
  • a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof can be administered to a subject in order to prevent a condition in the subject.
  • the condition prevented includes bone density loss, xerophthalmia, metabolic disorders, including dyslipidemia, atherosclerosis, and non-insulin dependent diabetes (NIDDM), cardiovascular disorders including hypertension, coronary artery disease, and myocardial perfusion, obesity and prostate cancer.
  • NIDDM non-insulin dependent diabetes
  • cardiovascular disorders including hypertension, coronary artery disease, and myocardial perfusion, obesity and prostate cancer.
  • III or pharmaceutically acceptable salts or prodrugs thereof is used to treat acne, male-pattern baldness, wasting diseases, hirsutism, hypogonadism, osteoporosis, infertility, impotence, obesity, and cancer.
  • one or more compounds provided herein are used to stimulate hematopoiesis.
  • one or more compounds provided herein are used for contraception.
  • provided herein are methods for treating a subject having a condition caused by androgen deficiency or a condition ameliorated by androgen replacement.
  • the methods include administering to the subject a therapeutically effective amount of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, and thereby treating the condition.
  • the condition is selected from among abdominal obesity, Alzheimer's disease, anemia, an arthritic condition, atherosclerosis, benign prostatic hyperplasia (BPH), cancer cachexia, cognitive decline, depression, metabolic syndrome, a muscular dystrophy, obesity, osteopenia, osteoporosis, a periodontal disease, prostate cancer, sexual dysfunction, sleep apnea, type II diabetes, bone fracture, frailty, wasting, aging skin, hypogonadism, post-menopausal symptoms in women, female sexual dysfunction, premature ovarian failure, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, arthritis and joint repair.
  • kits for treating, preventing, suppressing, inhibiting or reducing the incidence of muscle wasting in a subject include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat, prevent, suppress, inhibit or reduce muscle wasting in the subject.
  • the muscle wasting is caused by a condition selected from among andropause, a spinal muscular atrophy, a muscular dystrophy, myasthenia gravis, AIDS cachexia, cardiac cachexia, cancer cachexia, cancer, Chronic Obstructive Pulmonary Disease (COPD), emphysema, diabetes, HIV infection, acquired immunodeficiency syndrome (AIDS), sepsis, tuberculosis, renal failure, heart failure, cardiomyopathy, bed rest, disuse, inactivity, microgravity, malnutrition, sarcopenia and aging.
  • the one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is orally administered to the subject.
  • the compounds provided herein are used in a method for the treatment of muscular dystrophy, sarcopenia and frailty.
  • the methods include co-administering one or more than one compound provided herein with one or more agents selected from among interleukin-10 (IL-IO), interleukin-4 (IL-4), a TNF inhibitor, fluorinated 4-azasteroid derivatives, glial growth factors, acetylcholine receptor inducing activity (ARIA), heregulins, neu differentiation factor, and neuregulins (e.g., see U.S. Pat. Nos. 6,444,642 and 7,037,888).
  • IL-IO interleukin-10
  • IL-4 interleukin-4
  • TNF inhibitor fluorinated 4-azasteroid derivatives
  • glial growth factors e.g., glial growth factors, acetylcholine receptor inducing activity (ARIA), heregulins, neu differentiation factor, and neuregulins
  • ARIA acet
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the muscle- wasting condition.
  • methods for preventing a muscle wasting disorder in a subject which include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to preventing a muscle wasting disorder in the subject.
  • methods for suppressing a muscle wasting disorder in a subject which include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to suppress the muscle wasting disorder in a subject.
  • kits for reducing the incidence of a muscle wasting disorder in a subject which include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to suppress the muscle wasting disorder in a subject.
  • Methods for identifying a subject in need of treatment for a muscular wasting disease are known in the art. For example, a subject in need of treatment for a muscular wasting disease will often generate less electrical activity during muscle contraction as compared to a healthy subject and this can be detected by electromyography.
  • Alternative methods for diagnosis include, for example, blood tests and muscle biopsies. Suitably, blood tests can be run to determine the levels of various constituents of muscle and muscle fibers.
  • CPK creatine phosphokinase
  • Muscle biopsies also can be used to identify a subject in need of treatment for a muscular wasting disease.
  • a muscle biopsy a small piece of muscle tissue is removed surgically for laboratory analysis. The analysis can reveal abnormalities in the muscle, such as inflammation, damage, or infection.
  • the subject also can be diagnosed for a muscular wasting disease using magnetic resonance imagining (MRI).
  • MRI magnetic resonance imagining
  • cross-sectional images of muscle are generated by a magnetic field and radio waves. Similar to the muscle biopsy analysis, the image generated by an MRI can reveal abnormalities in the muscle, such as inflammation, damage, or infection.
  • Methods of improving muscle performance, size and/or strength are methods of increasing muscle performance, muscle size, muscle strength, or any combination thereof in a subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increase muscle performance, muscle size, and/or muscle strength in the subject.
  • kits for activating the function of the androgen receptor muscle tissue and blocking or inhibiting the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to activate the function of the androgen receptor in muscle tissue and to block or inhibit the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual.
  • one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is used to improve athletic performance.
  • the methods include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in a therapeutically effective amount to improve athletic performance.
  • one or more compounds provided herein are used, for example, to shorten the time normally needed to recover from physical exertion or to increase muscle strength. Athletes to whom one or more compounds provided herein can be administered include, but are not limited to, horses, dogs and humans.
  • one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is administered to an athlete engaged in a professional or recreational competition, including, but not limited to weight-lifting, body-building, track and field events, and any of various team sports.
  • provided herein are methods of treating, preventing, suppressing, inhibiting or reducing the incidence of osteoporosis, osteopenia, gluco- corticoid-induced osteoporosis or bone fracture in a subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat osteoporosis, osteopenia, glucocorticoid-induced osteoporosis or bone fracture in the subject.
  • the one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is co-administered with an effective amount of at least one other therapeutic agent, such as an estrogen or estrogen derivatives, alone or in combination with progestin or progestin derivatives; a bisphosphonate; an anti-estrogen; a selective estrogen receptor modulators (SERM); an QVjS 3 integrin receptor antagonist; a cathepsin inhibitor; a proton pump inhibitor; a PP AR ⁇ inhibitor; calcitonin; and osteoprotegerin.
  • the method is for the treatment of osteoporosis.
  • the method is for the treatment of osteopenia.
  • the method is for the treatment of glucocorticoid- induced osteoporosis.
  • the method is for the treatment of bone fracture.
  • provided herein are methods of activating the function of the androgen receptor in bone tissue and blocking or inhibiting the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to activate the function of the androgen receptor in bone tissue and to block or inhibit the function of the androgen receptor in the prostate of a male individual or in the uterus of a female individual.
  • provided herein are methods of increasing the strength of, or mass of a bone of a subject, or for promoting bone formation in a subject.
  • the methods include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to increase the strength of, or mass of a bone of a subject, or to promote bone formation in a subject.
  • provided herein are methods for preventing a bone- related disorder in a subject, which include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to prevent the bone-related disorder in the subject.
  • methods for suppressing a bone-related disorder in a subject which include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to suppress the bone-related disorder in the subject.
  • provided herein are methods for inhibiting a bone-related disorder in a subject, which include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to inhibit the bone-related disorder in the subject.
  • the bone-related disorder is osteoporosis. In another embodiment, the bone-related disorder is osteopenia, In another embodiment, the bone- related disorder is increased bone resorption. In another embodiment, the bone- related disorder is bone fracture. In another embodiment, the bone-related disorder is bone frailty. In another embodiment, the bone-related disorder is any combination of osteoporosis, osteopenia, increased bone resorption, bone fracture and bone frailty. In one embodiment, the osteoporosis results from androgen deprivation. In another embodiment, the osteoporosis follows androgen deprivation. In another embodiment, the osteoporosis is primary osteoporosis. In another embodiment, the osteoporosis is secondary osteoporosis.
  • the osteoporosis is postmenopausal osteoporosis. In another embodiment, the osteoporosis is juvenile osteoporosis. In another embodiment, the osteoporosis is idiopathic osteoporosis. In another embodiment, the osteoporosis is senile osteoporosis. 5. Methods of treating cancer In certain embodiments, one or more than one compound of Formula I, II or
  • Certain exemplary cancers include, but are not limited to, breast cancer, colorectal cancer, gastric carcinoma, glioma, head and neck squamous cell carcinoma, skin cancer, papillary renal carcinoma, leukemia, lymphoma, Li-Fraumeni syndrome, malignant pleural mesothelioma, melanoma, multiple myeloma, non-small cell lung cancer, synovial sarcoma, thyroid carcinoma, transitional cell carcinoma of urinary bladder, and prostate cancer, including, but not limited to prostatic hyperplasia.
  • the methods include administering one or more compounds provided herein in a therapeutically effective amount to treat the cancer.
  • administration of the one or more than one compound provided herein to a subject afflicted with a cancerous condition alleviates the cancerous condition by killing the cancerous cells.
  • administration of the one or more than one compound provided herein to a subject afflicted with a cancerous condition results in the inhibition of growth and/or metastasis of the cancer.
  • one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is administered in combination with one or more other therapeutic agents, such as, but not limited to, anti-proliferative agents, such as paclitaxel, a paclitaxel derivative, taxanes and vinca alkaloids, anti-tumor agents, such as mitomycin C or doxorubicin, hormones and antagonists, such as adreno-corticosteroids (prednisone), progestins (hydroxyprogesterone caproate, medroprogesterone acetate and megestrol acetate), estrogens (diethylstilbestrol and ethinyl estradiol), antiestrogens (tamoxifen), and androgens (testosterone propionate and fluoxymesterone), radionuclides, toxins and cytotoxic drugs, boron addends, chemotherapy agents, photodynamic therapy dyes, and antibiotics or combinations thereof to
  • toxins and cytotoxic drugs are known in the art that have cytotoxic effects on cells, any of which can be used in connection with the methods provided herein.
  • Examples of known cytotoxic agents useful in the present methods are listed, for example, in Goodman et al., "The Pharmacological Basis of Therapeutics," Sixth Edition, A. G. Gilman et al., eds., Macmillan Publishing Co., New York (1980).
  • adrenocortical suppressants such as mitotane; alkyl sulfonates, such as busulfan; ethylenimine derivatives, such as thiotepa; nitrosoureas, such as carmustine, lomustine, semustine and streptozocin; folic acid analogs, such as methotrexate; methyl hydrazine derivatives, such as procarbazine; nitrogen mustards, such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard and chlorambucil; purine analogs, such as mercaptopurine and thioguanine; pyrimidine analogs, such as fluorouracil, cytarabine and azaribine; substituted urea compounds, such as hydroxyurea; taxol; triazenes, such as dacarbazine; and vinca alkaloids, such as vinblast
  • Any antibiotic known in the art such as aminoglycosides, bleomycin, cephalosporins and other beta-lactam antibiotics, chloramphenicol, clindamycin, dactinomycin, daunorubicin, doxorubicin, fusidic acid, macrolides, metronidazole, mithramycin, mitomycin, mupirocin, penicillins, rifamycins, sulfonamides, tetracyclines, trimethoprim and beta-lactam inhibitors, can be included in the formulation.
  • Drugs that interfere with intracellular protein synthesis also can be used in the methods provided herein; such drugs are known to those skilled in the art and include puromycin, cycloheximide, and ribonuclease.
  • the methods provided herein also can include administration of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in combination with dyes used photodynamic therapy for the treatment of cancer, and used in conjunction with appropriate non-ionizing and ionizing radiation.
  • the use of porphyrins and other dyes used in photodynamic therapy can be used in the methods herein. Photodynamic therapy for the treatment of cancer is well known in the art (e.g., see U.S. Pat. Nos.
  • kits for treating, preventing, suppressing, inhibiting or reducing the incidence of prostate cancer in a subject include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in a therapeutically effective amount to treat the cancer.
  • the prostate cancer is androgen dependant prostate cancer.
  • the prostate cancer is androgen independent prostate cancer.
  • the prostate cancer is androgen independent, but androgen receptor dependant prostate cancer.
  • administration of the one or more than one compound provided herein to a subject afflicted with prostate cancer alleviates the prostate cancer by killing the cancerous cells. In one embodiment, administration of the one or more than one compound provided herein to a subject afflicted with prostate cancer results in the inhibition of growth and/or metastasis of the prostate cancer.
  • the one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is co-administered with another therapeutic agent, including, but not limited to, flutamide, bicalutamide and nilutamide, anti-tumor agent, such as toxins and cytotoxic drugs, which can be selectively targeted to react with prostate tumors by conjugating to a prostate tumor antigen, and radionuclides.
  • another therapeutic agent including, but not limited to, flutamide, bicalutamide and nilutamide, anti-tumor agent, such as toxins and cytotoxic drugs, which can be selectively targeted to react with prostate tumors by conjugating to a prostate tumor antigen, and radionuclides.
  • methods are provided for delaying the progression of prostate cancer in a subject suffering from prostate cancer. The methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to delay the progression of prostate cancer in
  • provided herein are methods for providing contraception in a subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to provide contraception in the subject.
  • provided herein are methods for providing contraception in a male subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to suppress sperm production in the subject, thereby effecting contraception in the subject.
  • the compounds provided herein inhibit spermatogenesis in a subject.
  • the method includes co-administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof with an androgen, such as 19- nortestosterone, 7omethyl-19-nortestosterone and 5 ⁇ -dihydro-testosterone.
  • the method includes co-administration of a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof that is an AR antagonist with testosterone.
  • provided herein are methods for providing hormone therapy to a subject.
  • the method includes administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to modulate androgen receptor activity, and thereby effect a change in an androgen-dependent condition.
  • methods for treating, preventing, suppressing, inhibiting or reducing the incidence of postmenopausal conditions in a subject include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the postmenopausal condition.
  • the postmenopausal condition treated by the method includes, but is not limited to, loss of libido, decreased sexual activity, diminished feelings of physical well-being, fatigue and hot flashes.
  • the method includes coadministering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof with one or more estrogens, such as estrone, 2-hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone, 15- ⁇ - hydroxyestrone, 16- ⁇ -hydroxyestrone, 16- ⁇ -hydroxyestrone, estradiol (17/?-estradiol), 2-hydroxy-estradiol, 2-methoxy-estradiol, 4-hydroxy-estradiol, 16-oxoestradiol, estriol, 16-epiestriol and 17-epiestriol or combinations thereof.
  • estrogens such as estrone, 2-hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone, 15- ⁇ - hydroxyestrone, 16- ⁇ -hydroxyestrone, 16- ⁇ -hydroxyestrone, estradiol (17/?-estradiol), 2-hydroxy-estradiol, 2-methoxy-estradiol, 4-hydroxy-
  • the method includes co-administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof with one or more estrogenic compound, such as estradiol valerate, estrone, estrone sulfate, an estrone sulfate piperazine salt or an ester thereof, or a synthetic estrogen.
  • estrogenic compound such as estradiol valerate, estrone, estrone sulfate, an estrone sulfate piperazine salt or an ester thereof, or a synthetic estrogen.
  • the method includes co-administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof with one or more agents selected from among alendronate, calcitonin, clodronate, clomiphene, clomiphene citrate, clonidine, conjugated estrogen, natural estrogen, synthetic estrogen, ethinyl estradiol, estradiol, enclomiphene, enclomiphene citrate, etidronate, ibandronate, medroxyprogesterone acetate, megestrol acetate, norethindrone acetate, pamidronate, progesterone, risedronate, tiludronate, zuclomiphene, zuclomiphene citrate and combinations thereof.
  • one or more agents selected from among alendronate, calcitonin, clodronate, clomiphene, clomiphene citrate, clonidine, conjugated estrogen, natural estrogen, synthetic estrogen,
  • Methods of treating hematopoietic disorders Also provided herein are methods of treating, preventing, suppressing, inhibiting or reducing the incidence of a hematopoietic disorder in a subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the hematopoietic disorder.
  • the hematopoietic disorder includes, but not limited to, anemia, leukemia, and hematopoietic conditions caused by bone marrow transplantation or chemo-/radiation therapy. Also provided are methods of increasing the number of red blood cells in a mammal in need thereof.
  • the method includes administering a therapeutically effective amount of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increase the number of red blood cells in a subject. Also provided are methods of treating anemia, thrombocytopenia or neutropenia in a subject. The methods include administering to the subject in need of such treatment one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat anemia, thrombocytopenia or neutropenia in the mammal.
  • one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is co-administered with a therapeutically effective amount of at least one hematopoietic cytokine.
  • the hematopoietic cytokine is selected from among erythropoietin, granulocyte-colony stimulating factor, granulocyte-macrophage-colony stimulating factor, interleukin-1 , interleukin-3, interleukin-4, interleukin-5, interleukin-7, interleukin-9, interleukin-1 1, macrophage- colony stimulating factor, stem cell factor and thrombopoietin.
  • the methods include administering a therapeutically effective amount of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to increase the serum EPO levels in the subject. 11.
  • Methods of treating neurodegenerative diseases and disorders provided herein are methods of treating, preventing, suppressing, inhibiting or reducing the incidence of a neurodegenerative disease or disorder in a subject.
  • the methods include administering to a subject having a neurodegenerative disease or disorder, one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the neurodegenerative disease or disorder.
  • the neurodegenerative disorder is Alzheimer's disease.
  • methods for preventing the onset or delaying the progression of Alzheimer's disease in patients include administering to a subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to prevent the onset or delay the progression of Alzheimer's disease in a subject.
  • the method can include co-administering an effective amount of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof with a therapeutically-effective amount of a compound that inhibits the formation or release of /3-amyloid. Any of the known inhibitors of the formation or release of /3-amyloid can be used in the methods, including, but not limited to, compounds described in U.S. Pat. App.
  • Methods of treating cognitive impairment Also provided herein are methods for treating, preventing, suppressing, inhibiting or reducing the incidence of cognitive impairment in a subject.
  • the methods include administering to a subject having cognitive impairment one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the cognitive impairment. 13.
  • Methods of treating depression include administering to a subject having cognitive impairment one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the cognitive impairment. 13.
  • the methods include administering to a subject having cognitive impairment one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat depression. 14.
  • Methods of treating obesity include administering to a subject having cognitive impairment one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat depression. 14.
  • the methods include administering to a subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat obesity.
  • a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof that is an AR agonist is used to treat a male subject with abdominal adiposity.
  • a compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof that is an AR antagonist is used to treat a female subject with abdominal obesity.
  • Methods of treating insulin resistance and diabetes Provided herein are methods of treating, preventing, suppressing, inhibiting or reducing the incidence of insulin resistance in a subject.
  • the methods include administering to a subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat insulin resistance.
  • methods of treating, preventing, suppressing, inhibiting or reducing the incidence of type 2 diabetes in a subject include administering to a subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat type 2 diabetes.
  • the method for treating diabetes includes co-administering an effective amount of one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof with an effective amount of an anti-diabetic drug, such as, but not limited to, thiazolidinedione-type drugs such as pioglitazone or rosiglitazone, sulfonylurea-type drugs, such as chlorpropamide, glimepiride, glipizide, glyburide or tolbutamide, a biguanide-type drug such as metformin, exenatide, acarbose, repaglinide, nateglinide, tolazamide or combinations thereof.
  • an anti-diabetic drug such as, but not limited to, thiazolidinedione-type drugs such as pioglitazone or rosiglitazone, sulfonylurea-type drugs, such as chlorpropamide, glimepiride,
  • the methods include administering to a subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat arterial hypertension, hyperinsulinemia, hyperglycaemia, type 2 diabetes or dyslipidaemia characteristically appearing with insulin resistance.
  • kits for treating, preventing, suppressing, inhibiting or reducing the incidence of sexual dysfunction in a subject include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat or prevent sexual dysfunction in the subject.
  • the sexual dysfunction is male erectile dysfunction.
  • the sexual dysfunction is impotence.
  • kits for increasing the libido of a male or female subject include administering to the subject in need thereof one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount that is effective to increase the libido of the subject.
  • Methods of treating arthritic conditions and inflammatory disorders Also provided herein are methods for treating, preventing, suppressing, inhibiting or reducing the incidence of an arthritic condition or inflammatory disorder.
  • the methods include administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective for the treatment or prevention of an arthritic condition or an inflammatory disorder.
  • the arthritic condition or inflammatory disorder is selected from among osteoarthritis, Behcet's disease, bursitis, tendonitis, CPPD deposition disease, carpal tunnel syndrome, Ehlers-Danlos syndrome, fibromyalgia, gout, infectious arthritis, inflammatory bowel disease, juvenile arthritis, lupus erythematosus, Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis imperfecta, osteonecrosis, polyarteritis, polymyalgia rheumatica, psoriatic arthritis, Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, Reiter's syndrome, rheumatoid arthritis, scleroderma and Sjogren's syndrome.
  • the method is for treating, preventing, suppressing, inhibiting or reducing the incidence of osteoarthritis, which includes administering one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective for the treatment or prevention of osteoarthritis.
  • the one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is co-administered with one or more drugs or agents known to treat or prevent arthritic conditions, such as corticosteroids, cytotoxic drugs (or other disease modifying or remission inducing drugs), gold treatment, methotrexate, aspirin, NSAIDs, COX-2 inhibitors and DMARDs (Disease-Modifying Anti-Rheumatic Drugs).
  • drugs or agents known to treat or prevent arthritic conditions such as corticosteroids, cytotoxic drugs (or other disease modifying or remission inducing drugs), gold treatment, methotrexate, aspirin, NSAIDs, COX-2 inhibitors and DMARDs (Disease-Modifying Anti-Rheumatic Drugs).
  • Exemplary DMARDs include, but are not limited to, leflunomide, auranofin, sulfasalazine, mycophenolate, myochrysine, cyclosporine, cyclophosphamide, azathioprine, chlorambucil, methotrexate, minocycline, penicillamine and hydroxychloroquine.
  • NSAIDs include, but are not limited to, diclofenac/misoprostol, diclofenac potassium, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefanamic acid, meloxicam, nabumetone, naproxen and naproxen sodium, oxaprozin, piroxicam, sodium sulindac and tolmetin.
  • COX-2 inhibitors include, but are not limited to, celecoxib, rofecoxib and valdecoxib. 18. Methods of improving lipid profile
  • provided herein are methods of improving the lipid profile in a subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to effect the lipid profile in the subject.
  • the one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof is co-administered with another agent, such as an anti-cholesterol agent or lipid-lowering agent, such as, but not limited to, ⁇ -hydroxy- ⁇ -methylbutyric acid, lactoferrin, cholestyramine, colestipol, colesevelam, nicotinic acid, f ⁇ bric acids (gemfibrozil, fenofibrate and clofibrate) and HMG-coA reductase inhibitors (lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerivastatin).
  • an anti-cholesterol agent or lipid-lowering agent such as, but not limited to, ⁇ -hydroxy- ⁇ -methylbutyric acid, lactoferrin, cholestyramine, colestipol, colesevelam, nicotinic acid, f ⁇ bric acids
  • provided herein are methods of reducing circulating lipid levels in a subject.
  • the method includes administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to reduce circulating lipid levels in the subject.
  • kits for treating, preventing, suppressing, inhibiting or reducing the incidence of atherosclerosis and its associated diseases including cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, and intestinal vascular disorders in a subject include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, alone or in combination with a selective estrogen receptor modulator (SERM) compound.
  • SERM selective estrogen receptor modulator
  • kits for treating, preventing, suppressing, inhibiting or reducing the incidence of a condition related to androgen decline such as in a male subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof in an amount effective to treat the condition related to androgen decline in the subject.
  • the condition is selected from among fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostate hyperplasia, anemia, alterations in mood and cognition, and prostate cancer.
  • kits for treating, preventing, suppressing, inhibiting or reducing the incidence of a condition related to androgen deficiency such as in a female subject.
  • the methods include administering to the subject one or more than one compound of Formula I, II or III or pharmaceutically acceptable salts or prodrugs thereof, in an amount effective to treat the condition related to androgen decline in the subject.
  • the condition is selected from among sexual dysfunction, decreased sexual libido, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer.
  • one or more compounds or compositions provided herein can be co-administered with one or more other therapeutic agents.
  • such one or more other therapeutic agents are designed to treat the same disease or condition as the one or more compounds or pharmaceutical compositions provided herein.
  • such one or more other therapeutic agents are designed to treat a different disease or condition as the one or more compounds or compositions provided herein.
  • such one or more other therapeutic agents are designed to treat an undesired effect of one or more compounds or compositions provided herein.
  • one or more compounds or compositions provided herein is co-administered with another therapeutic agent to treat an undesired effect of that other agent.
  • compounds or compositions provided herein and one or more other therapeutic agents are administered at the same time. In some embodiments, compounds or compositions provided herein and one or more other therapeutic agents are administered at the different times. In certain embodiments, compounds or compositions provided herein and one or more other therapeutic agents are prepared together in a single formulation. In certain embodiments, compounds or compositions provided herein and one or more other therapeutic agents are prepared separately.
  • therapeutic agents that can be co-administered with compounds or compositions provided herein include, but are not limited to, analgesics (e.g., acetaminophen); anti-inflammatory agents, including, non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-I inhibitors and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostan, and thyroid hormones); immuno-modulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., bisphosphonates, calcitonin, and estrogens); pros
  • therapeutic agents that can be co-administered with compounds or compositions provided herein include, but are not limited to, other modulators of nuclear hormone receptors or other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents; anti- osteoporosis agents; anti-obesity agents; anti-inflammatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; anti-platelet agents; anti-thrombotic and thrombolytic agents; cardiac glycosides; cholesterol/lipid lowering agents; mineralo- corticoid receptor antagonists; phosphodiesterase inhibitors; protein tyrosine kinase inhibitors; thyroid mimetics (including thyroid receptor agonists); anabolic agents; HIV or AIDS therapies; therapies used in the treatment of Alzheimer's and other cognitive disorders; therapies used in the treatment of sleeping disorders; antiproliferative agents; anti-rumor agents; bisphosphonates; estrogens; SERMs; anti- estrogens; catheps
  • Compounds 103 and 104 can be prepared in a similar fashion as described in Example 1 by using D-pyroglutamic acid as a starting material.
  • Compounds 109 and 110 can be prepared in a similar fashion as described in Example 1 by using 2-chloro-4-fiuoro-3-methylbenzonitrile as a starting material.
  • Example 6 Co-transfection assay - AR agonist/antagonist activity
  • Compound 102 (4-(2( ⁇ )-(l (-S)-hydroxyl-2,2,2-trifluoroethyl)- pyrrolidinyl)-2-trifluoromethylbenzonitrile) to activate or repress the ability of AR to induce gene expression was assessed using the cotransfection assay.
  • CV-I cells African green monkey kidney fibroblasts
  • DMEM Dulbecco's Modified Eagle Medium
  • charcoal resin-stripped fetal bovine serum then transferred to 96-well microtiter plates one day prior to transfection.
  • the CV-I cells were transiently transfected by calcium phosphate coprecipitation according to the procedure of Berger et al., J. Steroid Biochem. MoI. Biol. 41 : 733 (1992) with the following plasmids: pShAR (5 ng/well), MTV-LUC reporter (100 ng/well), pRS- ⁇ -Gal (50 ng/well) and filler DNA (pGEM; 45 ng/well).
  • the receptor plasmid, pRShAR contains the human AR under constitutive control of the SV-40 promoter, as more fully described in J.A. Simental et al., "Transcriptional activation and nuclear targeting signals of the human androgen receptor", J. Biol. Chem.
  • the reporter plasmid, MTV-LUC contains the cDNA for firefly luciferase (LUC) under control of the mouse mammary tumor virus (MTV) long terminal repeat, a conditional promoter containing an androgen response element. See e.g., Berger et al. supra.
  • MTV mouse mammary tumor virus
  • pRS- ⁇ -Gal coding for constitutive expression of E. coli ⁇ -galactosidase ( ⁇ -Gal) was included as an internal control for evaluation of transfection efficiency and compound toxicity.
  • PBS phosphate-buffered saline
  • Media containing reference compounds ⁇ e.g., progesterone as a PR agonist, mifepristone ((1 1/3,17 /3)-l l -[4-(dimethylamino)- phenyl]-17-hydroxy-17-(l-propynyl)estra-4,9-dien-3-one: RU486; Roussel Uclaf) as a PR antagonist; dihydrotestosterone (DHT; Sigma Chemical) as an AR agonist and 2-OH-flutamide (the active metabolite of 2-methyl-N-[4-nitro-3-(trifluoromethyl)- phenylj-pronanamide; Schering-Plough) as an AR antagonist; estradiol (Sigma) as an ER agonist and ICI 164,384 (N-butyl-3,17-dihydroxy-N-methyl-(7-alpha,17-beta)- estra-l,3,5(10)-triene-7-undecanamide;
  • NR normalized response
  • Antagonist activity was determined by testing the amount of LUC expression in the presence of a fixed amount of DHT as an AR agonist and progesterone as a PR agonist at the EC 50 concentration.
  • concentration of test compound that inhibited 50% of LUC expression induced by the reference agonist were quantified (IC 50 ).
  • the efficacy of antagonists was determined as a function (%) of maximal inhibition.
  • Compound 102 produced a concentration-dependent increase in luciferase activity in MDA-MB-453 cells that have endogenous expression of hAR. Compound 102 did not produce a concentration-dependent decrease in luciferase activity when tested in the presence of an EC 50 concentration of DHT (1 nM). Compound 102 was found to be a potent activator of hAR with an EC 50 of 3.1 nM and an efficacy of 59% when expressed relative to dihydrotestosterone (DHT, EC 50 of 2 nM and an efficacy of 100%), a natural ligand for AR. The ability of Compound 102 to activate transcription by other nuclear receptors also was evaluated.
  • DHT dihydrotestosterone
  • Agonist efficacy was determined relative to the appropriate reference agonist for each nuclear receptor.
  • Compound 102 did not transactivate (demonstrate agonist activity) through the other nuclear receptors evaluated (hPR-B, hGR, hMR, hER ⁇ , hRAR ⁇ , hLXR ⁇ , hFR ⁇ , hPPAR ⁇ , hPPAR ⁇ , hPPAR ⁇ ), except it very weakly activated hRXR ⁇
  • Compound 102 antagonized dexamethasone-induced activation of hGR (60% with an IC 50 of 1.6 ⁇ M) and progesterone-induced activation of hPR-B (74% with IC 50 of 280 nM), but not activation of hER ⁇ or hMR.
  • Example 7 Receptor Binding Assays Preparation of receptor proteins
  • a baculovirus expression plasmid including cDNA encoding the human androgen receptor (hAR) was prepared using standard techniques.
  • the expression plasmid was used to transfect Spodopter frugiperda-2 ⁇ (Sf-21 ) cells.
  • a suspension culture of uninfected Sf-21 cells was grown to a density of 1.2x10 6 cells/mL and then infected with the recombinant virus including hAR cDNA at a multiplicity of infection of 2.
  • the infected Sf-21 cells were incubated for 48 hours and then collected by centrifugation at 1000 x g for 10 minutes at 4 0 C.
  • the resulting cell pellets were resuspended in lysis buffer (50 mM potassium phosphate buffer, pH 7.0, 10 mM monothioglycerol, 5 mM DTT, 20 mM sodium molybdate, 1 mM PMSF, 1 ⁇ g/mL aprotinin, and 10 ⁇ g/mL leupeptin) and incubated for 15 minutes on ice.
  • the resuspended cell pellets were homogenized using a Dounce homogenizer and a B pestle. A volume of 2 M KCl was added to the homogenized cell pellets to a final concentration of 0.4 M.
  • the resulting receptor lysates were centrifuged at 100,000 x g for 60 min at 4 0 C and stored for use in binding assays. Binding Assays
  • Binding assay samples were prepared in separate mini-tubes in a 96-well format at 4 0 C. Each binding assay sample was prepared in a volume of 250 ⁇ L of Receptor- Assay Buffer (10% glycerol, 25 mM sodium phosphate, 10 mM potassium fluoride, 10 mM sodium molybdate, 0.25 mM CHAPS, 2 mM DTT and 1 mM EDTA, (adjusted to pH 7.5)) containing 50 ⁇ g of receptor lysate; 2-4 nM of [ 3 H]- dihydro- testosterone at 50-100 Ci/mmol; and either a reference compound or a test compound.
  • Receptor- Assay Buffer 10% glycerol, 25 mM sodium phosphate, 10 mM potassium fluoride, 10 mM sodium molybdate, 0.25 mM CHAPS, 2 mM DTT and 1 mM EDTA, (adjusted to pH 7.5)
  • Each reference compound and test compound was assayed at varying concentrations, ranging from 3.2 x 10 "10 to 10 "5 M. Each concentration of each reference compound and each test compound was assayed in triplicate. The assay samples were incubated for 16 hours at 4 0 C.
  • IC 50 values were determined using a 4-parameter fit, such as provided in commercially available software for curve fitting (e.g., Xlfit curve fitting software, IDBS Scientific Products, Guildford, UK). Typically all 4 parameters were floated to allow the best fit to converge.
  • the Kj values were determined by application of the Cheng-Prusoff equation to the IC 50 values using previously determined K d values for each specific ligand.
  • Compound 102 and other androgen modulating compounds including R 1 R- 2,2,2-trifluoro-l-[l-(4-nitro-3-trifluoromethyl-phenyl)-pyrrolidin-2-yl]-ethanol (LG0893410) and 5,i?-2,2,2-trifluoro-l-[l-(4-nitro-3-trifluoromethyl-phenyl)- pyrrolidin-2-yl]-ethanol (LG0893411):
  • Compound 102 demonstrated consistently higher potency, with a K; of 0.9 nM, by 3-6 fold than LG0893410 (Kj of 2.5 nM) and LG0893411 (K; of 5.7 nM) for binding to baculovirus expressed hAR protein. Higher potency indicates that Compound 102 can be administered at a lower dose to achieve equal therapeutic effect.
  • Example 8 Activation of hAR-responsive luciferase reporter
  • a functional assay was conducted to determine the ability of test substances to modulate gene expression via endogenous human androgen receptor (hAR) in a human cell line.
  • a luciferase reporter assay was utilized to establish the ability of test compounds to activate hAR-regulated gene expression in a human cell line containing endogenously expressed hAR (MDAMB-453 cells) transfected with an androgen- responsive luciferase reporter plasmid containing the cDNA for firefly luciferase.
  • MDA-MB-453 cells were transfected with a plasmid containing the cDNA for firefly luciferase (LUC) under the control of a conditional promoter containing hormone response elements recognized by AR (MMTV-LUC) and a P-galactosidase expression plasmid (pRS-(3-Gal) for normalization of transfection efficiency.
  • the reporter plasmid MMTVLUC contains the mouse Mammary Tumor Virus (MMTV) Long Terminal Repeat (LTR) conditional promoter containing hormone response elements recognized by hAR.
  • the luciferase response was calculated as:
  • Luciferase response Relative Luciferase Units (RLU)
  • ⁇ -gal rate ⁇ -gal O.D. 415 / ⁇ -Gal incubation time in minutes.
  • the mean of the normalized response at each concentration of compound was calculated.
  • the effective concentration that produced 50% of the maximum response (EC 50 ) was determined for each compound by interpolation between two concentrations spanning the midpoint of the concentration-response curve.
  • Agonist efficacy for test compounds was calculated as a percent of normalized response relative to the maximum normalized response by the reference agonist DHT.
  • Compound 102 activated AR-dependent gene expression.
  • Compound 102 having an EC50 of 2.8 nM, was 8.5 to 12.5 times more potent in activating hAR-responsive luciferase reporter than LG0893410 (ECs 0 of 24.2 nM) and LG089341 1 (EC 50 of 35.0 nM). Higher potency indicates that Compound 102 can be administered at a lower dose to achieve equal therapeutic effect.
  • a luciferase reporter co-transfection assay also was used to evaluate the ability of compounds provided herein to activate hAR regulated gene expression.
  • Compound 102 and other androgen receptor modulators including LG0893410 and LG089341 1 , were assayed to assess their ability to activate hAR regulated gene expression by transfecting CV-I cells, derived from African monkey kidney and lacking endogenous AR, with an expression plasmid containing the cDNA for the human AR (pRShAR) and the androgen-responsive luciferase reporter plasmid (MMTV-LUC).
  • CV-I cells were transiently transfected with pRShAR, a P- galactosidase expression plasmid (pRS-(3-Gal) for normalization of transfection efficiency, and the reporter plasmid MMTV-LUC using a non-liposomal formulation, the FuGENE 6 transfection reagent.
  • the mean of the normalized response at each concentration of compound was calculated.
  • the EC 50 was determined for each compound and agonist efficacy for test compounds was calculated as a percent of normalized response relative to the maximum normalized response by the reference agonist DHT.
  • Compound 102 having an EC 50 of 4.4 nM, was 3 to 5 times more potent in activating hAR than LG0893410 (EC 50 of 13.0 nM) and LG089341 1 (EC 50 of 23.3 nM). Higher potency indicates that Compound 102 can be administered at a lower dose to achieve equal therapeutic effect.
  • Compound 102 was tested to determine its ability to activate human skeletal oj-actin using the skeletal oactin promoter assay.
  • a mouse muscle cell line (C2C12) was transiently transfected with a human AR expression plasmid and a luciferase reporter plasmid containing the skeletal o ⁇ -actin promoter upstream of the luciferase cDNA.
  • C2C12 cells (at a concentration of 5 x 10 5 ) were seeded in a T25 flask and cultured for 24 hours. The cells were harvested by using trypsin and seeded at 6000 cells/well in 96-well plates.
  • Luciferase Assay Buffer After addition of Luciferase Assay Buffer to each well, the cells were assayed for luciferase activity using a luminometer to determine the level of transcriptional activation.
  • the effective concentration that produced 50% of the maximum response (EC 50 ) was determined from the concentration-response curve for the compound by interpolation between two concentrations spanning the midpoint of the concentration response curve.
  • Agonist efficacy for the test compound was calculated as a percent of luciferase response relative to the maximum luciferase response by the reference agonist DHT.
  • Compound 102 stimulated skeletal oactin promoter activity in a concentration-dependent manner. At a concentration of 1 x 10 "7 M, Compound 102 increased the promoter activity about 17.5 -fold compared to vehicle control. Compound 102 was not as potent as DHT but was equally efficacious. Compound 102 activated the skeletal ⁇ -actin promoter with an average EC 50 of 8.7 nM (DHT »1 nM) and efficacy of 93% of DHT. Compound 102 showed a strong AR-mediated stimulation of skeletal ⁇ -actin promoter activity in muscle cells, indicating that this compound likely up- regulated skeletal oactin production at the transcription level. Compound 102 stimulates Of-actin promoter activity in muscle cells in a manner similar to that of DHT, is highly potent (8.7 nM) and efficacious (93% compared to DHT).
  • Compound 102 was found to be 5-10 fold more potent in stimulating muscle cells than LG0893410 and LG089341 1 , having an EC 50 of 8.7 nM compared to 45.2 nM for LG0893410 and 85.6 nM for LG089341 1.
  • Compound 102 also was nearly as effective as the androgen agonist DHT in stimulating muscle cells (93% of DHT), while LG0893410 and LG089341 1 were much less effective (having an efficacy of 43% and 59%, respectively) in stimulating oactin gene transcription in muscle cells.
  • Example 11 - IL-6 Promoter Repression Assay IL-6 is an important bone resorption factor. Over-expression of IL-6 can cause severe bone loss in vivo. Reducing IL-6 production by bone cells would be therapeutically beneficial by reducing bone resorption.
  • Compound 102 and the androgen receptor modulators LG0893410 and LG089341 1 were tested to determine their ability to suppress TNF ⁇ -IL-l/3-induced IL-6 promoter activity in Saos-2 human osteoblast cells using a cotransfection assay.
  • a human osteoblast cell line (Saos-2) was transiently transfected with a human AR expression plasmid and a luciferase reporter plasmid containing the IL-6 promoter upstream of the luciferase cDNA.
  • Saos-2 cells were seeded at 6000 cells/well in 96-well plates.
  • FuGENE 6 reagent FuGENE 6 reagent (Roche, Indianapolis, IN) was used for transfection of the cells.
  • To each well was added 3.6 ⁇ g of the IL-6-LUC reporter plasmid and 0.7 ⁇ g of pCMV-hAR.
  • luciferase was stimulated by the cytokines Tumor Necrosis Factor o; (TNFo; 10 ng/mL) and Interleukin-1 beta (IL- 1/3, 1 ng/mL).
  • TNFo Tumor Necrosis Factor
  • IL- 1/3, 1 ng/mL Interleukin-1 beta
  • the effective concentration that produced 50% of the maximum response (EC 50 ) was determined from the concentration-response curve for the compound by interpolation between two concentrations spanning the midpoint of the concentration response curve.
  • Agonist efficacy for the test compound was calculated as a percent of luciferase response relative to the maximum luciferase response by the reference agonist DHT.
  • LG0893411 had an average IC 50 of 1.50 nM) and Compound 102 was found to have an efficacy of 97% of DHT.
  • Compound 102 suppresses IL-6 promoter activity in a manner similar to that of DHT, and is 3-4 fold more potent than LG0893410 and LG089341 1. These results suggest that Compound 102 down-regulates IL-6 production at the transcriptional level. Because Compound 102 suppresses IL-6 production by osteoblasts, it is expected to have a beneficial in vivo effect on bone by reducing bone resorption.
  • Liver microsomes are subcellular fractions that contain drug-metabolizing enzymes, such as cytochrome P450, flavin monooxygenases and UDP glucuronyl transferases. When the elimination of a drug occurs primarily by metabolism, the route of metabolism can significantly affect the drug's safety and efficacy, hence affecting the directions for use of the drug. Rat liver microsomes are a commonly used animal model for determination of drug metabolism (e.g., see Shayeganpour et al, Drug Metab Dispos 34 (1): 43-50 (2006)).
  • the metabolism of Compound 102 was evaluated in rat liver microsomes. The metabolism was initiated by adding 25 ⁇ L of cofactor (100 mM of glucose 6- phosphate, 20 mM of NADP, 20 mM of glucose-6-phosphate dehydrogenase, and 63 mM of UDPGA) to wells containing 50 ⁇ L of 5 mg/mL of rat liver microsomes and 425 ⁇ L of 0.59 mM of Compound 102 made in 100 mM phosphate buffer (pH 7.4) at 37 0 C. At 0, 5, 10 and 20 minutes, a 60 ⁇ L aliquot of the sample was withdrawn.
  • cofactor 100 mM of glucose 6- phosphate, 20 mM of NADP, 20 mM of glucose-6-phosphate dehydrogenase, and 63 mM of UDPGA
  • the unmetabolized test substance remaining in the sample was determined using HPLC and mass spectrometry and the half-life for degradation of the compound was calculated in minutes using curve fitting.
  • the half-life was determined to be 44.5 minutes (average value determined in 2 experiments with each experiment using triplicate measurements), demonstrating that Compound 102 has high metabolic stability, since it is only slowly metabolized.
  • High metabolic stability promotes oral bioavailability and reduces the burden of xenobiotic metabolites generated after administration of a therapeutically effective dose.
  • High metabolic stability is preferred for drugs that are intended for systemic administration, such as would be the case for treating diseases or conditions such as aplastic anemia; anorexia; arthritis, including inflammatory arthritis, rheumatoid arthritis, osteoarthritis and gout; arteriosclerosis; atherosclerosis; bone disease, including metastatic bone disease; bone damage or fracture, such as by accelerating bone fracture repair and/or stimulation of osteoblasts and/or stimulation of bone remodeling and/or stimulation of cartilage growth; distraction osteogenesis; reduced bone mass, density or growth; bone weakening, such as induced by glucocorticoid administration; musculoskeletal impairment (e.g., in the elderly); cachexia; cancer, including breast cancer and osteosarcoma; cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart
  • the orchidectomized male Sprague-Dawley rat model was used to assess the effects of Compound 102 on various reproductive, gonadotropin and musculoskeletal endpoints, including sex accessory organs, bone, serum gonadotropin levels and striated muscle in mature male rats.
  • Ostarine, a non-steroidal androgenic drug (Evans et al., J Clin Oncology 25: 9119 (2007)) was dosed at dosages similar to other test groups as a comparison. After the 14 th dose, venous blood was collected at 0, 1, 2, 4 and 6 hours after dosing. The blood samples were collected in EDTA-containing tubes (Becton Dickinson, Franklin Lakes, NJ). Approximately 24 hours after the last dose, animals were euthanized and seminal vesicle weights, ventral prostate weights, levator ani weights, preputial gland weights and blood samples were collected on necropsy. A. Serum and Plasma collection
  • test compound 102 For the preparation of all dose formulations, the appropriate amount of test compound (Compound 102) for the highest concentration to be administered was weighed. The compound was suspended in the formulation vehicle (5% Tween ® -80 polysorbate, 90% PEG-400 polyethylene glycol and 5% PVP-K30 polyvinylpyrrolidone). The suspension was sonicated for 15 minutes, and the resulting formulation was diluted using vehicle to obtain the proper volume and concentrations of the dosing materials to achieve a dosing volume of 1 mL/kg body weight.
  • formulation vehicle 5% Tween ® -80 polysorbate, 90% PEG-400 polyethylene glycol and 5% PVP-K30 polyvinylpyrrolidone
  • LH Luteinizing Hormone
  • Bound hormone was separated from free hormone by precipitation with a specific goat ant-rabbit serum (GARS from Antibodies, Inc., Davis, CA). An aliquot of 50 ⁇ L of 4% normal rabbit serum was added to each incubation tube, after which an additional 50 ⁇ L of a 1 : 10 GARS solution was added. The tubes were vortexed and incubated overnight at 4°C.
  • GAS goat ant-rabbit serum
  • the assay was terminated by centrifugation at 2,500 rpm for 30 minutes in a Sorvall RC 3C Plus centrifuge (rotor #H2000B) at 4 0 C. The supernatants were decanted and discarded and the pellets were counted in a 10-channel gamma-counter.
  • Serum osteocalcin a vitamin K-dependent, calcium binding protein
  • Serum osteocalcin is a biochemical marker that reflects bone formation activity (Gundberg, J Clin Ligand Assay 21 : 128-138 (1998)).
  • Serum osteocalcin was quantitated using an IRMA kit from Immutopics, Inc. (#50-1500, San Clemente, CA). The procedures were performed following the protocols supplied by the vendor (Rat Osteocalcin IRMA Kit Cat. #50-1500, 2005) except that 25 ⁇ L of sample was used instead of 5 ⁇ L of sample as suggested. The test uses two different antibodies to measure the serum osteocalcin.
  • the sample is incubated simultaneously with a bead-immobilized goat antibody that recognizes the mid-region C-terminal portion of the osteocalcin molecule and an I- labeled goat antibody that recognizes the amino terminal portion of the molecule. Osteocalcin present in the sample binds to the antibody immobilized on the bead and the radiolabeled antibody binds to the osteocalcin.
  • sample dilution 25 ⁇ L of sample and 400 ⁇ L of zero standard were dispensed into appropriately labeled tubes and vortexed. A 100 ⁇ L aliquot of standard, diluted control or diluted sample was dispensed into appropriately labeled tubes. 200 ⁇ L of I25 I-labeled Rat Osteocalcin Antibody was dispensed into all tubes followed by vortex mixing. One bead including the goat antibody was added to each tube, tilting the tube to prevent splashing of the tube contents by the addition of the bead. The tubes were sealed with Parafilm ® and incubated at room temperature for 18 to 24 hours. After the incubation period, the contents of each tube was aspirated, leaving the bead in the tube.
  • each tube was washed three times by dispensing 2 mL of wash solution into each tube and then completely removing the wash solution by aspiration. Each tube was counted in a gamma counter for one minute and the counts recorded. A standard curve was generated using the rat osteocalcin standards provided in the kit. The rat osteocalcin concentration (in ng/mL) of the diluted controls and diluted samples were read directly from the standard curve.
  • Plasma concentration time data for each animal were analyzed using WinNonlin (version 5.0, Pharsight WinNolin copyright ⁇ 1998-2005) by con- compartmental PK methods (Gibaldi et ah, Pharmokinetics (2 nd ed., Marcel Dekker, New York, NY, pp. 271-318 and 409-417 (1982)).
  • the elimination half life (t Vl ) was not estimated in this study due to the fact that plasma samples were collected at four time points (1, 2, 4 and 6 hours postdose).
  • the area under the plasma concentration curve (AUC) was calculated by the trapezoidal method.
  • the 0 hour plasma concentration was considered as the 24 hour plasma concentration at Day 14, assuming steady state, and used to estimate AUC 24 . Peak pharmacokinetic (PK) parameters were calculated and rounded to three decimal places.
  • Results were analyzed by analysis of transformed data (Box et al, J Roy Soc Series B 26: 21 1-252 (1964) and Box et al, Technometrics 16: 385-389 (1974). When necessary, transformations were performed to ensure that variances were homogeneous among groups and that the residuals of the one-way analysis of variance model followed a Gaussian (normal) distribution. When the analysis of variance reached significance, data were further evaluated by the Fisher's LSD test. A P value lee than 0.05 was considered as the minimum criterion to declare statistically significant differences. When possible, data were fitted to a modified four-parameter logistic equation (Ghosh et al, J Biopharm Stat 8: 645-665 (1998).
  • the model estimates ED50S in a logarithmic scale, since log ED 50 is a more robust estimate of the potency.
  • the model also provides an SE for the estimate that is used to calculate 95% confidence limits of the estimated potencies.
  • the following equation exemplifies the basic, reparametrized four-parameter logistic equation used in these studies:
  • the 14-day rat model is a short term in vivo model used to demonstrate the selectivity of androgen modulator compounds. Orchidectomy removes almost all of the endogenous circulating androgens in the rat.
  • Compound 102 was orally administered at levels of about 1.5 mg/kg/day, Compound 102 was able to maintain levator ani weight at sham-equivalent levels, while the same dose did not maintain the growth of ventral prostate or seminal vesicle at sham-equivalent level.
  • Compound 102 significantly increased levator ani weight above sham-equivalent levels, but still only restored the ventral prostate or seminal vesicles to approximately 50% of sham levels.
  • Compound 102 had an inhibitory effect on serum LH and was able to maintain sham-equivalent levels at a dose of 10 mg/kg/day. Compound 102 significantly decreased serum LH below sham equivalent levels at the highest tested dose (100 mg/kg/day).
  • Preputial gland weight measured as a marker of sebaceous gland activity, remained below vehicle equivalent levels for all doses of Compound 102 less than 10 mg/kg/day PO.
  • Compound 102 increased preputial gland weight above the sham level at the 30 mg/kg/day dose. The effect was statistically significant at this dose.
  • Serum osteocalcin tended to decrease with increasing dose of Compound 102, but the effects were not statistically significant at any tested dose. Orchidectomy has been reported to increase serum osteocalcin in male rats 2 weeks post-surgery (Ivaska et ai, J Biol Chem 279: 18361-18369 (2004)).
  • test compound was quantified in most of the plasma samples collected, although Compound 102 was below the limit of quantitation (BLQ) in a few plasma samples at 0.03 mg/kg/day and 0.1 mg/kg/day doses.
  • the mean PK parameters for Compound 102 are shown below in Table 1 : Table 1. Pharmacokinetic Parameters at Day 14 (Mean ⁇ SD).
  • the systemic exposures as measured by AUC 24 and C MAX , increased as the dose level increased and were roughly dose proportional.
  • the peak plasma concentrations were observed between 1 hour and 5 hour postdose.
  • Compound 102 stimulated muscle mass above sham equivalent levels yet restored the ventral prostate to less than 50% of sham equivalent levels. Ostarine was not as potent as Compound 102, restoring levator ani weight to sham equivalent levels at an exposure of 4 ⁇ g /mL. At exposures greater than 10 ⁇ g /mL, ostarine stimulated muscle mass above sham levels but did not restore ventral prostate to sham equivalents at any dose.
  • Compound 102 exhibited positive activity in musculoskeletal endpoints.
  • Compound 102 had dose proportional exposure and maintained levator ani weight at sham-equivalent levels at a dose of 2 mg/kg/day (AUC 24 : 0.2 ⁇ g /mL).
  • AUC 24 0.2 ⁇ g /mL
  • Compound 102 had lower efficacy (relative to sham) in sex accessory and sebaceous glands.
  • Compound 102 showed tissue selective activity toward the muscle endpoint.
  • Compound 102 showed lower potency for reducing the elevated LH levels in castrate rats ( ⁇ IO mg/kg/day) compared to increasing the reduced levator ani skeletal muscle mass in these animals (2 mg/kg/day). Compound 102 suppressed serum LH below sham-equivalent levels at high doses.
  • the comparator compound, ostarine a known non-steroidal selective androgen receptor modulator (SARM)
  • SARM non-steroidal selective androgen receptor modulator
  • estradiol was administered subcutaneously to one ovariectomized group at a dose of 0.1 mg/kg/day and testosterone propionate was administered subcutaneously to another ovariectomized group at a dose of 1 mg/kg/day.
  • Animals received subcutaneous injections of fluorochrome markers for bone histomorphometric analysis.
  • Alizarian Red S was prepared as a 3% solution and given at a dose of 30 mg/kg at the time of the baseline scan. Calcein was administered 10 days and 3 days prior to necropsy.
  • venous blood was collected via percutaneous jugular puncture from the rats at 0, 0.5, 1 , 2, 4 and 6 hours post-dosing.
  • the blood samples were collected into lithium-heparin tubes (Becton Dickinson, Franklin Lakes, NJ). Plasma fractions were collected for pharmacokinetic analysis.
  • rats were sacrificed by cardiac exsanguination, and blood was collected into serum separator tubes (Becton Dickinson), and the gastrocnemius muscle, plantaris muscle, uterus, clitoral glands, clitoris and inguinal fat pads were isolated, blotted and weighed individually.
  • Uterine weight measurements can be inaccurate in surgically ovariectomized rats due to the potential loss of uterine tissue at the tips of the uterine horns during removal of the ovaries. To minimize this variability, the length of the uterine horns was measured and the uterine weight was reported normalized to uterine length.
  • the left femur and lumbar vertebra L5 were wrapped in saline-soaked gauze and stored at -20°C for biochemical analysis.
  • the right femur and lumbar vertebrae L3-L4 were collected and stored in 70% ethanol for histomorphometry.
  • the right tibia was collected in formalin for histological analysis.
  • the left tibia was collected on dry ice and stored at -20°C for measurement of alkaline phosphatase activity.
  • A. Sample Preparation Compound 102 and ostarine individually were formulated in a solution containing 5% Tween-80 polysorbate, 90% PEG-400 polyethylene glycol, and 5% polyvinylpyrrolidone K30. The mixture was stirred and sonicated in a water bath for 30 minutes until the compound dissolved into a solution. After sonication, 1% carboxymethylcellulose (CMC) in water was added to the solution in a 9: 1 ratio (9 parts CMC/water solution to 1 part PEG-400/Tween-80/PVP).
  • CMC carboxymethylcellulose
  • Compound 102 and ostarine were administered orally in a volume of 4 mL/kg.
  • Reference compounds estradiol and testosterone propionate were formulated in a vehicle containing 70% polyethylene glycol and 30% DMSO (dimethyl sulfoxide) by volume.
  • Compounds were weighed and added to the appropriate volume of vehicle. The mixture was sonicated for several minutes to ensure that the compounds were thoroughly dissolved.
  • the reference compounds were administered subcutaneously in a volume of 0.4 mL/kg.
  • Dual X-ray absorptivity was performed on a Norland Peripheral Dual Energy X-Ray Absorptiometer (pDEXA Sabre, Norland Medical Systems, Orthmetrix, White Plains, NY). Prior to each use, the machine was calibrated using two phantoms supplied by the manufacturer. The machine calculated a coefficient of variation over the prior 16 calibrations to determine the measurement precision. The coefficient of variation for the quality control phantoms was between 0.47% to 0.57% during the course of the study. For in vivo DEXA measurements, the rats were anesthetized with isoflurane
  • BMC bone mineral content
  • BMD areal bone mineral density
  • BMC, BMD and bone length were measured by pDEXA on an entire femur after it was removed from the animal at the end of the experiment.
  • the coefficients of variation for the phantom standards were as described above for the in vivo measurements.
  • the coefficient of variation for repeated measurement of the isolated femur was less than 0.4% for the BMC and the BMD measurements.
  • Serum osteocalcin was quantitated using a kit from Immutopics (#50-1500, San Clemente, CA), using the procedures described above in Example 13.
  • femurs were collected for biomechanical analysis and thawed at room temperature prior to testing. Femurs were kept moist with saline throughout the preparation and testing. Total femoral length was measured with handheld digital calipers (Mitutoyo, Japan) and the midpoint of the femur was identified. The medial- lateral and anterior-posterior diameters were measured at the mid-femur with calipers. The whole femur was placed on a custom-designed 3-point bending fixture, consisting of stainless steel pins, 0.63 mm in diameter, with a span of 15 mm between the lower supports. A 5N preload was applied to the femurs at the mid-femur prior to the start of testing.
  • Lumbar vertebra L5 were thawed at room temperature prior to testing and were kept moist with saline throughout the preparation and mechanical testing.
  • the lateral and dorsal spinous processes were removed with a handheld grinding/cutting tool (Dremel, Mount Prospect, IL) and the cranial end of the vertebral body was mounted on an aluminum slab with a cyanoacrylate glue.
  • the stub was mounted in the grips of a low speed saw (Isomet, Buehler Ltd., Lake Bluff, IL) and two plane- parallel section were cut at 4 mm intervals, effectively removing the growth plates and primary spongiosa from the ends of the vertebral body.
  • the resultant cylinder of bone was measured with handheld digital calipers in the cranial/caudal, medial/lateral and dorsal/ventral directions. Specimens were placed on the loading platen and a compressive load was applied at 20 mm/minute in the cranial/caudal direction until failure of the vertebral body. Peak load and peak displacement were measured directly from the load cell and the crosshead, respectively. Stiffness was calculated from the slope of the linear region of the load/displacement curve. Energy absorption was calculated as the area under the load/displacement curve. As with the femur, the organ level properties described above were normalized to yield intrinsic of material properties of the lumbar spine using standard engineering equations. F.
  • the lumbar vertebral bodies were trimmed, dehydrated and embedded in polymethyl methacrylate.
  • the femur were trimmed into thirds (proximal, mid-shaft and distal). All were dehydrated in ethanol and the distal and mid-shaft were embedded in polymethyl methacrylate.
  • the proximal portion of the femur was dried and stored.
  • Section of the vertebral bodies and femur mid-shaft were cut with precision bone saws, the section mounted on plastic slides and the sections were ground to about 30-40 ⁇ m in thickness using a bone grinding system.
  • the sections were polished and the fluorochrome makers were viewed in the unstained section.
  • the section from the lumbar vertebral bodies were used for histomorphometric indices of cancellous bone, while the sections of the femur mid-shafts were used for histomorphometric indices of cortical bone.
  • %dLS periosteal and endocortical percent double labeled surface
  • %sLS periosteal and endocortical percent single-labeled surface
  • %MS periosteal and endocortical percent mineralization surface
  • MAR periosteal and endocortical new bone area
  • Compound 102 significantly increased body weight, gastrocnemius weight and plantaris weight, indicating anabolic activity on skeletal muscle. At the dose tested, testosterone tended to increase body weight gain more than vehicle, but this increase did not achieve statistical significance. Compound 102 significantly increased weight gain from baseline compared to vehicle at all the doses tested. Ostarine significantly increased weight gain compared to vehicle at the mid and high dose levels, but at the low dose there was no significant difference from vehicle. At the maximally effective does for Compound 102 (0.3 mg/kg) and ostarine (0.3 mg/kg), the increased change in body weight was similar (mean change of +66 grams and +65 grams, respectively). The increase in body weight resulted from an increase in lean tissue mass rather than in increase in fat mass.
  • Inguinal fat pad weight was used as a representative fat pad to assess the effects of drug on body fat. Inguinal fat pad weight was increased by ovariectomy (OVX + vehicle vs. Sham, P ⁇ 0.01) and treatment with either estradiol or testosterone reduced the elevated fat pad weight due to ovariectomy. However, neither Compound 102 nor ostarine significantly affected inguinal fat pad weight at any dose. The weights of two skeletal muscles, gastrocnemius and plantaris, were measured to assess the effects of drugs on lean body mass. Compound 102 had equal or greater efficacy on muscle endpoints in comparison to testosterone or ostarine.
  • Clitoral gland weight was measured to assess the effect of drugs on sebaceous glands. Testosterone significantly increased clitoral gland weight at the dose tested. Neither Compound 102 nor ostarine affected clitoral gland weight at the low dose tested. Both Compound 102 and ostarine increased clitoral gland weight at the high dose tested. At the mid dose (0.3 mg/kg), which was maximally effective for increasing body weight and skeletal muscle mass, Compound 102 and ostarine had similar activity which was only slightly above the sham level. The relatively small increase versus sham was statistically significant (P ⁇ 0.05) for mid dose ostarine whereas Compound 102 did not quite achieve statistical significance versus sham at the mid dose (P>0.05).
  • Uterine weight measurements can be inaccurate in surgically ovariectomized rats due to the potential loss of uterine tissue at the tips of the uterine horns during removal of the ovaries. To minimize this variability uterine weight was normalized to uterine length. Both Compound 102 and ostarine increased uterine weight to length ratio above estrogen deficient OVX controls in a dose dependent manner. Uterine weight to length ratio was significantly (P ⁇ 0.01) less than sham operated controls at both the low and mid dose of Compound 102. Uterine weight to length ratio was significantly (P ⁇ 0.01) less than sham operated controls for low dose ostarine but not for mid dose ostarine (P>0.05).
  • Compound 102 increased uterine weight to length ratio significantly less than ostarine (P ⁇ 0.01) at both the low and mid dose.
  • uterine weight to length ratio was significantly (P ⁇ 0.01) increased above sham levels for Compound 102 and ostarine but the compounds were not significantly different from each other (P>0.05 high dose ostarine versus high dose Compound 102).
  • ii. Dual Energy X-Ray Absorptiometry Compound 102 significantly increased bone mineral density (BMD) and bone mineral content (BMC) at the lumbar spine after 12 weeks of dosing. At the 0.3 mg/kg dose, Compound 102 was the most efficacious treatment in this experiment.
  • Testosterone did not significantly increase lumbar spine BMD or BMC. Estradiol increased spinal bone density but did not alter bone mineral content, which is consistent with a different mechanism of action. Ostarine had similar activity relative to Compound 102. Compound 102 also was effective at the femur, a site comprised of both cortical and cancellous bone. Compound 102 significantly increased femur BMD and BMC and was the most efficacious compound tested in this experiment. Ostarine had similar activity as Compound 102, while testosterone was less efficacious and did not significantly increase BMD or BMC above vehicle levels. Similar to the results at the lumbar spine, estradiol significantly increased femur BMD but not BMC. iii. Biochemical Assays
  • Serum osteocalcin a marker for bone turnover, was significantly suppressed by Compound 102 and ostarine in a dose-dependent manner. Estradiol and testosterone also suppressed osteocalcin below the levels of vehicle-treated OVX controls. Alkaline phosphatase activity from isolated tibiae was significantly increased by
  • Compound 102 significantly suppressed mineralizing surface and bone formation rates in a does-dependent manner. This decrease indicates a suppression of bone remodeling consistent with changes in serum osteocalcin. The net effect was an increase in trabecular bone volume with the 0.3 mg/kg dose of Compound 102. Ostarine and estradiol had similar activity on trabecular bone remodeling and bone volume. Testosterone had qualitatively similar effects, but the changes were small and only achieved statistical significance for the mineralizing surface measurement. vi. Pharmacokinetic Parameters
  • Compound 102 is a selective androgen receptor modulator that has beneficial effects on bone and muscle in a model of postmenopausal osteoporosis.
  • Compound 102 significantly increased cortical bone mass, density, strength, stiffness and periosteal bone formation rates when orally administered to osteopenic female rats. These changes demonstrate that Compound 102 has anabolic activity at cortical bone sites and are inconsistent with a compound that predominately inhibits resorption, such as estradiol.
  • Compound 102 suppressed cancellous bone turnover while increasing trabecular bone volume and increasing bone mineral density at the lumbar spine.
  • Compound 102 increased gastrocnemius muscle weight, plantaris muscle weight and body weight without affecting inguinal fat pad weight.
  • Compound 102 demonstrated some tissue selectivity, as it was more efficacious on muscle and bone at the 0.3 mg/kg dose than testosterone, yet has reduced activity on the clitoral gland, clitoris or uterus relative to testosterone.
  • the effects of Compound 102 on bone and muscle were similar to the comparator compound ostarine, although Compound 102 had increased potency, reaching maximal efficacy at an exposure substantially lower than that of ostarine.
  • the data indicate that Compound 102 has beneficial effects in an animal model of osteoporosis.
  • Example 17 Pharmacokinetics of Compound 102 in Sprague Dawley Rats
  • Compound 102 The pharmacokinetics of Compound 102 following repeat oral administration for 15 days was evaluated in Sprague-Dawley rats. A total of 30 rats (15 males and 15 females) were divided into three dose groups (5 males/5 females). Compound 102 was suspended in a vehicle of 2% Tween 90: 0.5% carboxymethyl cellulose (high viscosity) (50:50, v/v) at concentrations of 0.25, 0.75 and 2.5 mg/mL and animals were dosed via oral gavage at 1, 3 and 10 mg/kg once daily for 15 days. Tap water and a diet of rodent chow were provided to the animals ad libitum.
  • Compound 102 showed dose proportional increase of systemic exposure at 1 , 3 and 10 mg/kg dose levels.
  • Female rats showed higher systemic exposure than male rats on Day 1 and Day 15.
  • the systemic exposure of Compound 102 did not decrease with repeat administration.
  • the systemic exposure in male rats was higher on Day 15 than on Day 1 , while that in female rats remained similar between the two days.
  • a Sprague Dawley Rat model was used to study oral toxicity and toxicokinetics. Animals were assigned to groups by a stratified randomization scheme designed to achieve similar group mean body weights and the groups were randomly assigned to a dosing to provide control of bias. A total of 154 Sprague- Dawley rats were assigned to dose groups as shown in Table 5 below.
  • All animals were dosed via oral gavage once daily for 14 days.
  • the animals were evaluated for changes in clinical signs (mortality/morbidity observations, twice daily), cage side observations (general appearance and behavior), food consumption (quantitatively measured by weighing), body weights, clinical pathology indices including serum chemistry, hematology, coagulation and urinalysis, and other parameters.
  • Blood samples were collected for toxicokinetics analysis from Groups 6- 10 at various time points on Days 1 and 14 (Group 6 4 hours post dose; Groups 7-10 at 1, 4 and 12 hours or 2, 8 and 24 hours). The animals were fasted for at least 8 hours prior to blood collections for serum chemistry and urine collection.
  • Serum chemistry parameters tested included alanine aminotransferase, total protein, aspartate aminotransferase, albumin, alkaline phosphatase, globulin, gamma-glutamyl- transferase, albumin/globulin ratio, lactate dehydrogenase, glucose, total bilirubin, cholesterol, urea nitrogen, triglycerides, creatinine, sodium, calcium, potassium, phosphorus and chloride.
  • Hematology parameters analyzed included red blood cell count, reticulocyte count, hemoglobin concentration, red blood cell distribution width, mean corpuscular volume, mean platelet volume, mean corpuscular hemoglobin concentration, white blood cell count and differentials and mean corpuscular hemoglobin.
  • Urinalysis parameters included color/character, ketones, specific gravity, bilirubin, pH, occult blood, protein, glucose and microscopies. Main study animals were euthanized on Day 15. At termination, a full necropsy was conducted and all tissues were collected, preserved, processes and examined microscopically from Groups 1 and 5, and target organs (liver and kidney) from Groups 2-4, by a veterinary pathologist certified by the American College of Veterinary Pathologists.
  • Control vehicle included Peg-400 (Sigma P-3265), Tween ® 80 (Sigma P-8074) and PVP-K30 (polyvinyl pyrrolidone or povidone K-30, Spectrum PN P 1454) at a ratio of 90:5:5, w/w/w.
  • Appropriate amounts of Compound 102 were added to the control vehicle to produce homogeneous dosing solutions/suspensions. Results Once daily, oral gavage administration of Compound 102 for 14 days to
  • Sprague-Dawley rats at 10, 100, 300 or 700 mg/kg/day was not associated with test article-related morbidity or early death. There were only two 700 mg/kg/day female animals that died early on Days 3 and 9, but gross and microscopic findings indicate that each death was the result of esophageal perforation during dosing. Clinical observation data indicated an increased incidence and frequency in rough hair coat and nasal discharge for animals dosed with Compound 102 (particularly for the female animals at > 100 mg/kg/day). Male and female animals dosed with Compound 102 exhibited an increased weight gain compared to control animals, which was an anticipated pharmacological effect of this class of compounds.
  • Clinical pathology alterations attributed to administration of Compound 102 included minimal changes in alkaline phosphatase (ALP), phosphorus, triglycerides, potassium, reticulocyte counts, red cell distribution width, platelet counts and mean platelet volume at doses ⁇ IO mg/kg/day. A minimal prolongation in prothrombin time was also noted for male and female animals dosed with Compound 102 at 300 and 700 mg/kg/day. Because of the small magnitude of change, none of these alterations were considered to be adverse. There were no test article-related findings in the urinalysis data. There were no macroscopic or microscopic changes that were considered to be related to Compound 102. Dose-dependent liver weight increases were not correlated with appreciable increases in hepatocellular size or liver pathology.
  • Triglyceride concentrations were minimally lower in male rats dosed at ⁇ 00 mg/kg/day and in female rats dosed at >300 mg/kg/day (changes were statistically significant). Potassium levels were minimally higher in male rats dosed at >300 mg/kg/day and in female rats dosed at > 100 mg/kg/day. These minimal changes in potassium and triglycerides were not considered to be adverse. Intergroup differences in other serum chemistry parameters were sporadic or of a magnitude of change commonly observed in laboratory rats undergoing similar study procedures and were not considered to the test article-related. Hematology
  • Compound 102 had higher reticulocyte counts and red cell distribution width. These changes were not accompanied by decreased indicators of circulating erythrocyte mass (i.e., red blood cells, hemoglobin or hematocrit) nor were the changes noted in male animals. Platelet counts also were increased with statistical significance for female animals dosed at >100 mg/kg/day and for males dosed at 10 mg/kg/day and 700 mg/kg/day. Increases in mean platelet count also were noted for the female animals (statistically significant for Groups 3 and 5). The test article increases in reticulocyte counts, RDW, platelets and MPV were minimal and not considered to be adverse. Intergroup differences in the hematology chemistry parameters were sporadic or of a magnitude of change commonly observed in laboratory rats undergoing similar study procedures and were not considered to the test article-related.
  • Coagulation A minimal prolongation in prothrombin time was noted for male and female animals dosed with Compound 102 at 300 and 700 mg/kg/day. The magnitude of this change was not considered to be adverse.
  • liver weight increases were not correlated with appreciable increases in hepatocellular size and the liver pathology was negligible.
  • group mean absolute organ weights There were, compared to concurrent controls, several statistically significant increases in group mean absolute organ weights. Those absolute organ weights with dose-dependent increases were limited to the liver of both sexes. The group mean body weights were increased compared to the controls at every dose level. Despite the increased body weights, liver to body weight ratios were increased in a doe-dependent manner for males and females at 100 mg/kg/day and above
  • Test article-related clinical signs included increased observations of rough hair coat and nasal discharge for animals dosed at > 100 mg/kg/day. Increases in body weight also were observed for male and female animals dosed with Compound 102. Non-adverse clinical pathology alterations related to administration of >10 mg/kg/day Compound 102 were noted for alkaline phosphatase, phosphorus, triglyceride, potassium, reticulocyte counts, red cell distribution width, platelet counts, mean platelet volume and prothrombin time.
  • All animals were dosed via nasal gavage once daily for 14 consecutive days. The first day of dosing was designated Day 1 for all animals. The animals were evaluated for clinical signs (evaluation of mortality and morbidity, twice daily), cage side observations and food consumption (once daily), body weight (Days 1, 8 and 14), physical examination (Day -5 and post dosing following the 13/24 hour toxicokinetic collection on Day 14), ophthalmic examination (prestudy and owing the Day 13/24 hour toxicokinetic collection on Day 14), and clinical pathology parameters (serum chemistry, hematology and coagulation on Days -3 and 14), urine samples were collected during necropsy (Day 15) for urinalysis. Blood samples were collected for toxicokinetic analysis at 1, 2, 4, 8, 12 and 24 hours post dose on Days 1 and 13.
  • Blood samples for evaluation of serum chemistry, hematology and coagulation parameters were collected from all animals on Days -3 and 14. Urine samples were obtained by bladder puncture during necropsy. The animals were fasted for at east 8 hours prior to blood collections for serum chemistry.
  • Serum chemistry parameters included alanine aminotransferase (ALT), total protein, aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), albumin, globulin, albumin/globulin ratio, lactate dehydrogenase (LD), glucose, total bilirubin, cholesterol, urea nitrogen (BUN), creatinine, triglycerides, sodium, calcium, potassium, phosphorus, chloride and carbon dioxide.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • ALP alkaline phosphatase
  • GTT gamma-glutamyltransferase
  • albumin albumin
  • globulin albumin/globulin ratio
  • lactate dehydrogenase LD
  • glucose total bilirubin
  • cholesterol cholesterol
  • BUN urea nitrogen
  • Hematology parameters included red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), red cell distribution width, reticulocyte count, platelet count, mean platelet volume (MPV) and white blood cell count.
  • Coagulation parameters included prothrombin time (PT) and activated partial thromboplastin time.
  • Urinalysis parameters included color/character, specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood and microscopies. Results
  • Serum cholesterol concentration was decreased on Day 14 in all animals receiving Compound 102. The reductions in cholesterol did not appear to be adverse.
  • the female animal dosed with 450 mg/kg had elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, without increased lactate dehydrogenase (LD). This animal also had barely noticeable minimal single cell hepatocellular necrosis in the liver. Taken together, these changes affecting a high-dose animal suggested a possible relationship with the test article.
  • platelet count There was a dose-independent decrease in platelet count at all Compound 102 dose levels.
  • platelet counts were lower (approximately 14% to 38%) relative to Day -3 in both male and female animals in the 5, 50 and 150 mg/kg-dosed groups and the female high-dose animal (450 mg/kg). Platelet count on Day 14 was marginally increased for the high-dose and control males and reduced approximately 5% for the control female relative to Day -3. Although the platelet counts were lower for 7 of 8 Compound 102-dosed animals on Day 14 (relative to Day -3) and to the control animals, the clinical significance of this finding was not considered adverse.
  • Compound 102-related effects were identified at the 5, 50, 150 and 450 m/kg dose levels in both sexes, including increased body weight (consistent with the expected pharmacological activity of this class of compounds), decreased serum cholesterol concentration and platelet count, and prolonged prothrombin time. These changes were generally dose-independent and considered non-adverse.
  • Macroscopic (gross necropsy) observations possibly related to Compound 102 were limited to brown discoloration of the adrenals and decreased thymus size at 150 and 450 mg/kg in both sexes. There was no apparent microscopic correlate to the brown adrenals. Minimal to mild lymphoid cortical depletion of the thymus in males at 150 mg/kg and above and in females at 50 mg/kg and above and decreased thymus size were considered secondary to stress and not a direct toxicologic effect.
  • the systemic exposure of Compound 102 increased with increasing dose up to 450 mg/kg in both sexes. Following repeat administration of Compound 102 the systemic exposure was decreased on Day 13 (relative to Day 1 exposure), and the decrease in systemic exposure was more pronounced in the high-dose groups. There was no noticeable sex difference in the Day 1 and Day 13 toxicokinetic parameters.
  • the NOAEL was 450 mg/kg for the males and 150 mg/kg for the females (based on findings that in the 450 mg/kg-dosed female ALT and AST were elevated and there were histologic changes to the liver).
  • a NOEL was not achieved as a result of increased body weight, decreased serum cholesterol concentration and platelet count, and prolonged prothrombin time present in all Compound 102-dosed groups.
PCT/US2008/013657 2007-12-21 2008-12-12 Selective androgen receptor modulators (sarms) and uses thereof WO2009082437A2 (en)

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ES08865188T ES2413504T3 (es) 2007-12-21 2008-12-12 Moduladores selectivos del receptor de andrógeno (SARM) y usos de los mismos
CN200880127182.1A CN101945853B (zh) 2007-12-21 2008-12-12 选择性雄激素受体调节剂(sarm)及其应用
BRPI0821090A BRPI0821090B8 (pt) 2007-12-21 2008-12-12 moduladores seletivos de receptores de androgênio (sarms) e uso do mesmo
US12/734,993 US8354446B2 (en) 2007-12-21 2008-12-12 Selective androgen receptor modulators (SARMs) and uses thereof
SI200830973T SI2222636T1 (sl) 2007-12-21 2008-12-12 Selektivni modulatorji androgenskega receptorja (SARMS) in njihove uporabe
JP2010539438A JP5539221B2 (ja) 2007-12-21 2008-12-12 選択的アンドロゲン受容体モジュレーター（ｓａｒｍ）およびその使用
EP20080865188 EP2222636B1 (en) 2007-12-21 2008-12-12 Selective androgen receptor modulators (sarms) and uses thereof
DK08865188T DK2222636T3 (da) 2007-12-21 2008-12-12 Selektive androgenreceptormodulatorer (SARMS) og anvendelser deraf
CA2709677A CA2709677C (en) 2007-12-21 2008-12-12 Selective androgen receptor modulators (sarms) and uses thereof
PL08865188T PL2222636T3 (pl) 2007-12-21 2008-12-12 Selektywne modulatory receptorów androgenowych (SARM) i ich zastosowania
MX2010006972A MX2010006972A (es) 2007-12-21 2008-12-12 Moduladores selectivos de receptores de andrógenos (sarm) y usos de los mismos.
TW97148899A TWI437003B (zh) 2007-12-21 2008-12-16 選擇性雄性素受體調節物（ＳＡＲＭs）及其用途
CL2008003825A CL2008003825A1 (es) 2007-12-21 2008-12-19 Compuestos derivados de 4-pirrolidinbenzonitrilo, moduladores selectivos de receptores de androgeno; composicion farmaceutica; kit farmaceutico; y su uso en el tratamiento de una enfermedad o trastorno seleccionada de piel envejecida, enfermedad de alzheimer, anemia, artritis, gota, arterosclerosis, enfermedad osea, entre otras.
ARP080105633A AR092284A1 (es) 2007-12-21 2008-12-19 MODULADORES SELECTIVOS DE RECEPTORES DE ANDROGENOS (SARMs) Y USOS DE LOS MISMOS
US13/694,063 US8748633B2 (en) 2007-12-21 2012-10-23 Selective androgen receptor modulators (SARMs) and uses thereof
HRP20130552AT HRP20130552T1 (en) 2007-12-21 2013-06-17 Selective androgen receptor modulators (sarms) and uses thereof
US14/263,237 US9139520B2 (en) 2007-12-21 2014-04-28 Selective androgen receptor modulators (SARMs) and uses thereof
US14/827,228 US9675583B2 (en) 2007-12-21 2015-08-14 Selective androgen receptor modulators (SARMS) and uses thereof
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