Deciphering the selective androgen receptor modulators paradigm

Expert Opinion on Drug Discovery

Volumn 8, Issue 2, 2013, Pages 191-218

  Zhang, Xuqing ^a   Sui, Zhihua ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

Androgen; Androgen receptor; Androgen responsive tissues; Selective androgen receptor modulators; Tissue selectivity

Indexed keywords

5 AMINOTHIOPHENE DERIVATIVE; AC 262536; ACP 105; AMINOALKYLAMIDE; ANILINE; ARYLPROPIONAMIDE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; BICALUTAMIDE; BISPHENOL DERIVATIVE; BMS 564929; DIGLYCIDIC ETHER DERIVATIVE; ENOBOSARM; GSK 971086; HYDANTOIN DERIVATIVE; IMIDAZOLECARBOXAMIDE; JNJ 28330835; JNJ 37654032; LGD 2226; LGD 2941; LGD 3303; LGD 4033; MK 0773; N (4 HETEROCYCLYLPHENYL)CYCLIC AMINE DERIVATIVE; OXADIAZOLE DERIVATIVE; OXADIAZOLYLALKYLINDOLE DERIVATIVE; OXOOXAZOLIDINYLBENZONITRILE DERIVATIVE; PYRAZOLE DERIVATIVE; QUINOLINONE DERIVATIVE; RAD 140; RAD 35010; S 101479; S 40305; S 40503; S 42; SELECTIVE ANDROGEN RECEPTOR MODULATOR; SPIROTHIOHYDANTOIN DERIVATIVE; TETRAHYDROCYCLOPENTA[B]INDOLE DERIVATIVE; TETRAHYDROQUINOLONE DERIVATIVE; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; YK 11;

BINDING AFFINITY; BIOLOGICAL ACTIVITY; BONE DENSITY; CACHEXIA; CLINICAL EVALUATION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG MARKETING; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MUSCLE ATROPHY; NONHUMAN; OSTEOPOROSIS; PRIORITY JOURNAL; PROSTATE HYPERTROPHY; REVIEW;

ANIMALS; CLINICAL TRIALS AS TOPIC; DRUG DISCOVERY; HUMANS; LIGANDS; MODELS, ANIMAL; RECEPTORS, ANDROGEN;

EID: 84872722597     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2013.741582     Document Type: Review

References (155)

1. Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev 1987;8:1-28
2. Perez-Lopez FR, Larrad-Mur L, Kallen A, et al. Gender differences in cardiovascular disease: hormonal and biochemical influences. Reprod Sci 2010;17:511-31
3. Matsumoto T, Shiina H, Kawano H, et al. Androgen receptor functions in male and female physiology. J. Steroid. Biochem. Mol. Biol 2008;109:236-41
4. Liverman CD, Blazer DG. Testosterone and aging: clinical research directions. Institute of Medicine report Natl Acad Press; Washington, D.C: 2004
5. Diamond TH. Pharmacotherapy of osteoporosis in men. Exp Opin Pharmacother 2005;6:45-58
6. Vanderschueren D, Vandenput L, Boonen S. Androgen and bone. Endocr Rev 2004;25:389-425
7. Cameron DR, Braunstein GD. Androgen replacement therapy in women. Fertil Steril 2004;82:273-89 (Pubitemid 39092019)
8. Buster JE, Kingsberg SA, Aguirre O, et al. Low-dose estradiol spray to treat vasomotoe symptoms: a randomized controlled trial. Obstet Gynecol 2005;105:944-52
9. Bocklandt S, Vilain E. Sex differences in brain and behavior: hormones versus genes. Adv Genet 2007;59:245-66
10. Leder B. Gonadal steroids and bone metabolism in men. Curr Opin Endocrinol Diabetes Obes 2007;14:241-6 (Pubitemid 46684480)
11. Chang C, Saltzman A, Yeh S, et al. Androgen receptor: an overview. Crit Rev Eukaryot Gene Expr 1995;5:97-125
12. Dehm SM, Tindall DJ. Androgen receptor structural and functional elements: role and regulation in prostate cancer. Mol Endocrinol 2007;21:2855-63 (Pubitemid 350223500)
13. Li J, Al-Azzawi F. Mechanism of androgen receptor action. Maturitas 2009;63:142-8
14. Claessens F, Denayer S, Van Tilborgh N, et al. Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nucl Recept Signal 2008;6:e008
15. Alen P, Claessens F, Verhoeven G, et al. The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription. Mol Cell Biol 1999;19:6085-97 (Pubitemid 29399314)
16. Bevan CL, Hoare S, Claessens F, et al. The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol 1999;19:8383-92 (Pubitemid 30414032)
17. Gao T, Marcelli M, McPhaul MJ. Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol 1996;59:9-20 (Pubitemid 27014137)
18. Jenster G, van der Korput HA, van Vroonhoven C, et al. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol 1991;5:1396-404
19. Simental JA, Sar M, Lane MV, et al. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem 1991;266:510-18 (Pubitemid 21906153)
20. Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev 2002;23:175-200 (Pubitemid 34299023)
21. Verrijdt G, Haelens A, Claessens F. Selective DNA recognition by the androgen receptor as a mechanism for hormone-specific regulation of gene expression. Mol Genet Metab 2003;78:175-85 (Pubitemid 36335810)
22. Ylikomi T, Bocquel MT, Berry M, et al. Cooperation of proto-signals for nuclear accumulation of estrogen and progesterone receptors. Embo J 1992;11:3681-94
23. Gioeli D, Black BE, Gordon V, et al. Weber MJ. Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol 2006;20:503-15 (Pubitemid 43291205)
24. Tilley WD, Buchanan G, Hickey TE, et al. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res 1996;2:277-85 (Pubitemid 26074615)
25. Wang C, Uchida T. Androgen receptor gene mutations inprostate cancer. Nippon Hinyokika Gakkai Zasshi 1997;88:550-6 (Pubitemid 27251497)
26. Tanner TM, Denayer S, Geverts B, et al. A 629RKLKK633 motif in the hinge region controls the androgen receptor at multiple levels. Cell Mol Life Sci 2010;67(11):1919-27
27. Wong C, Kelce WR, Sar M, et al. Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. J Biol Chem 1995;270:19998-20003
28. Kallio PJ, Poukka H, Moilanen A, et al. Androgen receptor-mediated transcriptional regulation in the absence of direct interaction with a specific DNA element. Mol Endocrinol 1995;9:1017-28
29. Pfahl M. Nuclear receptor/AP-1 interaction. Endocr Rev 1993;14:651-8 (Pubitemid 23320391)
30. Ye X, Han SJ, Tsai SY, et al. Roles of steroid receptor coactivator (SRC)-1 and transcriptional intermediary factor (TIF) 2 in androgen receptor activity in mice. Proc Natl Acad Sci USA 2005;102:9487-92 (Pubitemid 40981708)
31. Langley E, Kemppainen JA, Wilson EM. Intermolecular NH2-/carboxyl- terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity. J Biol Chem 1998;273:92-101 (Pubitemid 28042181)
32. Thompson J, Saatcioglu F, Janne OA. et al. Disrupted amino-and carboxyl-terminal interactions of the androgen receptor are linked to androgen insensitivity. Mol Endocrinol 2001;15:923-35 (Pubitemid 32510639)
33. Quigley CA, Tan JA, He B, et al. Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH2-and carboxyl-terminal interaction. Mech Ageing Dev 2004;125:683-95 (Pubitemid 39482399)
34. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-59
35. Kazi M, Geraci SA, Koch CA. Considerations for the diagnosis and treatment of testosterone deficiency in elderly men. Am J Med 2007;120:835-40 (Pubitemid 47451287)
36. Kicman AT. Pharmacology of anabolic steroids. Br J Pharmacol 2008;154:502-21 (Pubitemid 351744954)
37. Nieschlag E. Testosterone treatment comes of age: new options for hypogonadal men. Clin Endocrinol (Oxf) 2006;65:275-81
38. Wang C, Nieschlag E, Swerdloff R, et al. ISA ISSAM EAU EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Impot Res 2009;21:1-8
39. Wang C, Nieschlag E, Swerdloff RS, et al. ISA ISSAM EAU EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2009;12:5-12
40. Zhi L, Martinborough E. Selective androgen receptor modulators (SARMs). Annu Rep Med Chem 2001;36:169-80 (Pubitemid 33804597)
41. Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J Clin Endocrino Metab 1999;84:3459-62 (Pubitemid 30645191)
42. Jones JO. Improving selective androgen receptor modulator discovery and preclinical evaluation. Expert Opin Drug Discov 2009;4:981-93
43. Haendler B, Cleve A. Recent developments in antiandrogens and selective androgen receptor modulators. Mol Cell Endocrinol 2012;352:79-91
44. Mohler ML, Bohl CE, Jones A, et al. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem 2009;52:3597-617
45. Rodolfo C, Philip T. Selective androgen receptor modulators in drug discovery: medicinal chemistry and therapeutic potential. Curr Top in Med Chem 2006;6:245-70
46. Mohler M L, Nair VA, Hwang DJ, et al. Nonsteroidal tissue selective androgen receptor modulators: a promising class of clinical candidates. Expert Opin Ther Pat 2005;15:1565-85 (Pubitemid 41671618)
47. Zhang X, Lanter JC, Sui Z. Recent advances in the development of selective androgen receptor modulators. Expert Opin Ther Pat 2009;19:1239-58
48. Mohler ML, He Y, Hwang DJ, et al. Nonsteroidal tissue selective androgen receptor modulators. Volume 39 In Nuclear Receptors as Drug Targets Wiley-VCH; Weinheim: Germany: 2008. p. 249-304.Chapter 8
49. Narayanan R, Mohler ML, Bohl CE, et al. Selective androgen receptor modulators in preclinical and clinical development. Nucl Recept Signaling 2008;6:e010
50. Dalton JT, Mukherjee A, Zhu Z, et al. Discovery of nonsteroidal androgens. Biochem Biophys Res Commun 1998;244(1):1-4 (Pubitemid 28419889)
51. Radius Health, Inc. Preparation of oxooxazolidinylbenzonitrile derivatives and analogs for use as selective androgen receptor modulators. WO 2012047617; 2012
52. Radius Health, Inc. Preparation of oxadiazole compounds as selective androgen receptor modulators. US 20120004270; 2012
53. Aragon pharmaceuticals. Preparation of spiro thiohydantoin compounds as androgen receptor modulators. WO 2011103202; 2011
54. The University of British Columbia. Bisphenol derivatives as androgen receptor modulators and their preparation and use for the treatment of diseases. WO 2011082488; 2011
55. Orion, Co. Preparation of pyrazole-and imidazole-carboxamide derivatives as modulators of androgen receptor. WO 2011051540; 2011
56. Astrazeneca. Bicyclic derivatives for use in the treatment of androgen receptor associated conditions and their preparation. WO 2009081197; 2009
57. Sumitomo Chemical. Preparation of 5-aminothiophene derivatives as selective androgen receptor modulators. WO 2010126167; 2010
58. Radius Health, Inc. Preparation of oxadiazolylalkylindoles as selective androgen receptor modulators. WO 2010118287; 2010
59. Consiglio Nazionale delle Ricerche Italy; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori. Preparation of aminoalkylamide and oxoimidazolidine derivatives and related compounds as modulators of androgen receptor. WO 2010092546; 2010
60. University of British Columbia. Diglycidic ether derivatives as androgen receptor modulators and their preparation, pharmaceutical compositions and use in the treatment of cancers. WO 2010000066; 2010
61. Eli Lilly and Company. Preparation of tetrahydrocyclopenta[b]indole as androgen receptor modulators. WO 2009140448; 2009
62. Takeda Pharmaceutical. Preparation of N-(4-heterocyclylphenyl) cyclic amine compounds as androgen receptor modulators. WO 2009133861; 2009
63. Yin D, Gao W, Kearbey JD, et al. Pharmacodynamics of selective androgen receptor modulators. J Pharmacol Exp Ther 2003;304:1334-40 (Pubitemid 36254449)
64. Gao W, Kearbey JD, Nair VA, et al. Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5a-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: New approach for benign prostate hyperplasia. Endocr 2004;145:5420-8 (Pubitemid 39564578)
65. Chen J, Hwang DJ, Bohl CE, et al. A selective androgen receptor modulator for hormonal male contraception. J Pharmacol Exp Ther 2005;312:546-53 (Pubitemid 40189551)
66. Jones A, Chen J, Hwang DJ, et al. Preclinical characterization of a (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2- hydroxy-2-methyl-propanamide: a selective androgen receptor modulator for hormonal male contraception. Endocr 2009;150:385-95
67. Kearbey JD, Gao W, Narayanan R, et al. Selective androgen receptor modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats. Pharm Res 2007;24(2):328-35 (Pubitemid 46084804)
68. Jones A, Hwang DJ, Duke CB III, et al. Nonsteroidal selective androgen receptor modulators enhance female sexual motivation. J Pharmacol Exp Ther 2010;334:439-48
69. University of Tennessee Research Foundation. Phenoxypropionic acid benzamides and related compounds as selective androgen receptor modulators (SARMs) for treating diabetes, diseases associated with diabetes, and other disorders. WO 2008127717; 2008.study NCT00467844 http://clinicaltrials.gov
70. News release from GTx, Inc. on June 06, 2011: GTx announces agreement with FDA on Phase III clinical development plan evaluating OstarineTM (GTx-024) for the prevention and treatment of muscle wasting in patients with non-small cell lung cancer
71. GTx announces investigational OstarineTM (MK-2866) met the primary endpoint in the Phase II cancer cachexia clinical trial. Oral podium presentation at the 2009 Annual Meeting of the Endocrine Society; Washington
72. Ostrowski J, Kuhns JE, Lupisella JA, et al. Pharmacological and X-raystructural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats. Endocr 2007;148:4-12 (Pubitemid 46023448)
73. Li JJ, Sutton JC, Nirschl A, et al. Discovery of potent and muscle selective androgen receptor modulators (SARMs) through scaffold modifications. J Med Chem 2007;50:3015-25 (Pubitemid 47001244)
74. Nirschl AA, Zou Y, Krystek Jr SR, et al. N-Aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation. J Med Chem 2009;52:2794-8
75. Edwards JP, Higuchi R, Jones T. Androgen receptor modulator compounds and methods. US 2000 6017924; 2000
76. Edwards JP, West SJ, Pooley CL, et al. New nonsteroidal androgen receptor modulators based on 4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g] quinolinone. Bioorg Med Chem Lett 1998;8:745-50 (Pubitemid 28160033)
77. Edwards JP, Higuchi RI, Winn DT, et al. Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)-2H-pyrano[3,2-g]quinolin-2-one. Bioorg Med Chem Lett 1999;9:1003-8 (Pubitemid 29179897)
78. Higuchi RI, Edwards JP, Caferro TR, et al. 4-Alkyl-and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: potent, nonsteroidal androgen receptor agonists. Bioorg Med Chem Lett 1999;9:1335-40 (Pubitemid 29207457)
79. Riedmaier I, Tichopad A, Reiter M, et al. Influence of testosterone and a novel SARM on gene expression in whole blood of Macaca fascicularis. J Steroid Biochem Mol Biol 2009;114:167-73
80. Miner JN, Chang W, Chapman MS, et al. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocr 2007;148:363-73 (Pubitemid 46021469)
81. Martinborough E, Shen Y, Oeveren A, et al. Substituted 6-(1-pyrrolidine) quinolin-2(1H)-ones as novel selective androgen receptor modulators. J Med Chem 2007;50:5049-52 (Pubitemid 47585701)
82. Vajda EG, Lopez FJ, Rix P, et al. Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3Hpyrrolo-[ 3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator. J Pharmacol Exp Ther 2009;328:663-70
83. Vajda EG, Hogue A, Griffiths KN, et al. Combination Treatment with a selective androgen receptor modulator (SARM) and a bisphosphonate has additive effects in osteopenic female rats. J Bone Min Res 2009;24:231-40
84. Kudwa AE, Lopez FJ, McGivern RF, et al. A selective androgen receptor modulator enhances male-directed sexual preference, proceptive behavior, and lordosis behavior in sexually experienced, but not sexually naive, female rats. Endocri 2010;15:2659-68
85. Ligand presents first-in-human Phase I data on lead SARM molecule LGD-4033. A poster presentation at the 14th International Congress of Endocrinology; Kyoto, Japan
86. Vajda EG, Marschke K, van Oeveren A, et al. LGD-4033 builds muscle and bone with reduced prostate activity and maybe beneficial in age-related frailty. According to the following link from Ligand. Avaialble from (http://www.ligand.com/upload/File/publications/SARM%20LGD 4033%20Poster%20November%202009. pdf
87. Basaria S, Collins L, Sheffield-Morre M, et al. Safety and tolerability of LGD-4033, a novel non-steroidal oral selective androgen receptor modulator (SARM), in healthy men. J Gerontol A Biol Sci 2012; PubMed ID 22459616 Epub ahead of print
88. Hanada K, Furuya K, Yamamoto N, et al. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol Pharm Bull 2003;26(11):1563-9 (Pubitemid 41699636)
89. Furuya K, Yamamoto N, Ohyabu Y, et al. The novel non-steroidal selective androgen receptor modulator S-101479 has additive effects with bisphosphonate, selective estrogen receptor modulator, and parathyroid hormone on the bones of osteoporotic female rats. Biol Pharm Bull 2012;35(7):1096-104
90. Piu F, Gardell LR, Son T, et al. Pharmacological characterization of AC-262536, a novel selective androgen receptor modulator. J Steroid Biochem Mol Biol 2008;109:129-37
91. Schlienger N, Lund BW, Pawlas J, et al. Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators. J Med Chem 2009;52:7186-91
92. Miller CP, Shomali M, Lyttle CR, et al. Design, synthesis, and preclinical characterization of the selective androgen receptor modulator (SARM) RAD140. ACS Med Chem Lett 2011;2:124-9
93. Miller CP, Bhaket P, Muthukaman N, et al. Synthesis of potent, substituted carbazoles as selective androgen receptor modulators (SARMs). Bioorg Med Chem Lett 2010;20:7516-20
94. Schmidt A, Harada SI, Kimmel DB, et al. Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands. J Biol Chem 2010;284:36367-76
95. Kim Y, Spencer KL, Hanney B, et al. Preparation of carbonylaminobenzimidazoles as selective androgen receptor modulators. WO 2004041277; 2004
96. Kim Y, Close J, Duggan ME, et al. N-(pyridin-3-yl)-2-phenylbutanamides as androgen receptor modulators. WO 2006060108; 2006
97. Schmidt A, Kimmel DB, Bai C, et al. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem 2010;285:17054-64
98. Yarrow JF, Conover CF, McCoy SC, et al. 17b-Hydroxyestra-4,9,11-trien-3- one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate. Am J Physiol 2011;300:E650-60
99. Kanno Y, Hikosaka R, Zhang SY, et al. (17a,20E)-17,20-[(1- Methoxyethylidene) bis (oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11) is a partial agonist of the androgen receptor. Biol Pharm Bull 2011;34:318-23
100. Min L, Yanase T, Tanaka T, et al. A novel synthetic androgen receptor ligand, S42, works as a selective androgen receptor modulator and possesses metabolic effects with little impact on the prostate. Endocrinol 2009;150:5606-16
101. Mitchell HJ, Dankulich WP, Hartman GD, et al. Design, synthesis, and biological evaluation of 16-Substituted 4-azasteroids as tissue-selective androgen receptor modulators (SARMs). J Med Chem 2009;52:4578-81
102. A study of the safety and efficacy of MK-0773 in women with sarcopenia. Available from: http://clinicaltrials.gov/ct2/show/NCT00529659
103. Levy N, Tatomer D, Herber CB, et al. Differential regulation of native estrogen receptor-regulatory elements by estradiol, tamoxifen, and raloxifene. Mol Endocrinol 2008;22(2):287-303 (Pubitemid 351185932)
104. Ball LJ, Levy N, Zhao X, et al. Cell type-and estrogen receptor-subtype specific regulation of selective estrogen receptor modulator regulatory elements. Mol Cell Endocrinol 2009;299(2):204-11
105. Maggiolini M, Picard D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J Endoc 2010;204:105-14
106. Buijsman RC, Hermkens PH, van Rijn RD, et al.Teerhuis NM. Non-steroidal steroid receptor modulators. Curr Med Chem 2005;12:1017-75 (Pubitemid 40667791)
107. Wright AS, Douglas RC, Thomas LN, et al. Androgen-induced regrowth in the castrated rat ventral prostate: role of 5alpha-reductase. Endocrinol 1999;140:4509-15 (Pubitemid 30666115)
108. Matzkin H, Soloway MS. Immunohistochemical evidence of the existence and localization of aromatase in human prostatic tissues. Prostate 1992;21:309-14 (Pubitemid 23045293)
109. Tsugaya M, Harada N, Tozawa K, et al. Aromatase mRNA levels in benign prostatic hyperplasia and prostate cancer. Int J Urol 1996;3:292-6 (Pubitemid 26264303)
110. Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 2004;25:45-71 (Pubitemid 38292038)
111. He Y, Yin D, Perera M, et al. Novel nonsteroidal ligands with high binding affinity and potent functional activity for the androgen receptor. Eur J Med Chem 2002;37:619-34 (Pubitemid 34874896)
112. Narayanan R, Coss CC, Yepuru M, et al. Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways. Mol Endocrinol 2008;22(11):2448-65
113. Obligacion R, Murray M, Ramzan I. Drug-metabolizing enzymes and transporters: expression in the human prostate and roles in prostate drug disposition. J Androl 2006;27:138-50
114. Barbier O, Bélanger A. Inactivation of androgens by UDP-glucuronosyltransferases in the human prostate. Best Pract Res Clin Endocrinol Metab 2008;22:259-70 (Pubitemid 351611947)
115. Kim J, Wu D, Hwang DJ, et al. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl) -propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. J Pharmacol Exp Ther 2005;315:230-9 (Pubitemid 41380516)
116. Gao W, Reiser PJ, Coss CC, et al. Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats. Endocrinol 2005;146(11):4887-97 (Pubitemid 41446627)
117. Nobes JP, Langley SEM, Klopper T, et al. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int 2012;109:1495-502
118. Singh R, Artaza JN, Taylor WE, et al. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinol 2006;147:141-54 (Pubitemid 43004269)
119. Pihlajamaa P, Zhang FP, Saarinen Li, et al. The phytoestrogen genistein is a tissue-specific androgen receptor modulator. Endocrinol 2011;152:4395-405
120. Allioli N, Vincent S, Vlaeminck-Guillem V, et al. TM4SF1, a novel primary androgen receptor target gene over-expressed in human prostate cancer and involved in cell migration. Prostate 2011;71:1239-50
121. Kerry MJ, Lee SB, Nicole HI, et al. Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis. Diabetes 2012;61:1072-81
122. Asthana S, Bhasin S, Butler RN, et al. Masculine vitality: pros and cons of testosterone in treating the andropause. J Ger A Biol Sci Med Sci 2004;59:461-5 (Pubitemid 38649937)
123. Genazzani AR, Pluchino N. Androgen replacement therapy and cardiovascular function. Climacteric 2009;12:102-7
124. Murphy KT, Lynch GS. Update on emerging drugs for cancer cachexia. Expert Opin Emerging Drugs 2009;14:619-32
125. Dodson S, Baracos VE, Jatoi A, et al. Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. Annu Rev Med 2011;62:265-79
126. Anonymous. Contraceptive efficacy of testosterone-induced azoospermia in normal Men. World health organization task force on methods for the regulation of male fertility. Lancet 1990;336:955-9
127. Anonymous. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal Men. World health organization task force on methods for the regulation of male fertility. Fertil Steril 1996;65:821-9
128. Wang C, Swerdloff RS. Male hormonal contraception. Am J Obstet Gynecol 2004;190:S60-8 (Pubitemid 38561495)
129. Wang C, Swerdloff RS. Male contraception in the 21st century. Endocr Updates 1999;5:303-19
130. Sharpe RM, Donachie K, Cooper I. Re-evaluation of the intratesticular level of testosterone required for quantitative maintenance of spermatogenesis in the rat. J Endo 1988;117:19-26
131. Bradley AD. Update on the development of male hormonal contraceptives. Curr Opin Investig Drugs 2007;8:318-23
132. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-44 (Pubitemid 29081307)
133. Buena F, Swerdloff RS, Steiner BS, et al. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. Fertil Steril 1993;59:1118-23 (Pubitemid 23139689)
134. Ansong KS, Punwaney RB. An assessment of the clinical relevance of serum testosterone level determination in the evaluation of men with low sexual drive. J Urol 1999;162:719-21 (Pubitemid 29436858)
135. Davidson JM, Chen JJ, Crapo L, et al. Hormonal changes and sexual function in aging men. J Clin Endo Met 1983;57:71-7 (Pubitemid 13065447)
136. Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. J Urol 2000;163:460-3 (Pubitemid 30060493)
137. Carani C, Bancroft J, Granata A, et al. Testosterone and erectile function, nocturnal penile tumescence and rigidity, and erectile response to visual erotic stimuli in hypogonadal and eugonadal men. Psychoneuroendocrinology 1992;17:647-54 (Pubitemid 23043127)
138. Shah NM, Pisapia DJ, Maniatis S, et al. Visualizing sexual dimorphism in the brain. Neuron 2004;43(3):313-19 (Pubitemid 39061124)
139. Cameron DR, Braunstein GD. Androgen replacement therapy in women. Fertil Steril 2004;82:273-89 (Pubitemid 39092019)
140. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944-52 (Pubitemid 40571010)
141. Allan GF, Tannenbaum P, Sbriscia T, et al. A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats. Endocrine 2007;32:41-51 (Pubitemid 350242546)
142. Saad F, Aversa A, Isidori AM, et al. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabe Rev 2012;8:131-43
143. Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol 2005;63:280-93 (Pubitemid 41233445)
144. Heufelder AE, Saad F, Bunck MC, et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009;30:726-33
145. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. Jama 2008;299:39-52
146. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:2560-75
147. Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 2010;33:1186-92
148. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996;335:1-7 (Pubitemid 26230806)
149. Bauer JM, Sieber CC. Sarcopenia and frailty: a clinician's controversial point of view. Exp Gerontol 2008;43:674-8
150. Evans WJ, Morley JE, Argiles J, et al. Cachexia: a new definition. Clin Nutr 2008;27:793-9
151. Hersberger LG, Shipley EG, Meyer RK. Myotrophic activity of 19-nortestosterone and other steroids determined by modified levator ani muscle method. Proc Soc Exp Biol Med 1953;83(1):175-80
152. Nejishima H, Yamamoto N, Suzuki M, et al. Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia. Prostate 2012;72:1580-7
153. Zhang X, Li X, Allan GF, et al. Design, synthesis, and in vivo SAR of a novel series of pyrazolines as potent selective androgen receptor modulators. J Med Chem 2007;50:3857-69 (Pubitemid 47292049)
154. Allan GF, Sbriscia T, Linton O, et al. A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats. J Steroid Biochem Mol Biol 2008;110:207-13
155. Smithkline Beecham, Co. Chemical Compounds. WO 2008121602; 2008