title: 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.
abstract: The pharmacologic effects of (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) were characterized in male rats as an animal model of hormonal male contraception. S-23 showed high binding affinity (inhibitory constant = 1.7 +/- 0.2 nm) and was identified as a full agonist in vitro. In castrated male rats, the ED50 of S-23 in the prostate and levator ani muscle was 0.43 and 0.079 mg/d, respectively. In intact male rats treated for 14 d, S-23 alone suppressed LH levels by greater than 50% at doses greater than 0.1 mg/d, with corresponding decreases in the size of the prostate but increases in the size of levator ani muscle. In intact male rats treated for up to 10 wk with S-23 and estradiol benzoate (EB; necessary to maintain sexual behavior in rats), S-23 showed biphasic effects on androgenic tissues and spermatogenesis by suppressing serum concentrations of LH and FSH. EB alone showed no effect on spermatogenesis. In the EB + S-23 (0.1 mg/d) group, four of six animals showed no sperm in the testis and zero pregnancies (none of six) in mating trials. After termination of treatment, infertility was fully reversible, with a 100% pregnancy rate observed after 100 d of recovery. S-23 increased bone mineral density and lean mass but reduced fat mass in a dose-dependent manner. This is the first study to show that a selective androgen receptor modulator combined with EB is an effective and reversible regimen for hormonal male contraception in rats. The beneficial effects of S-23 on the muscle, tissue selectivity, and favorable pharmacokinetic properties make it a strong candidate for use in oral male contraception.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, L. M. Parks Hall, Room 242, Columbus, Ohio 43210, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Jones
authors.forename: Jiyun
authors.initials: J
authors.lastname: Chen
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Hwang
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
mesh_terms: D000728:Androgens; D000813:Anilides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D003272:Contraceptive Agents, Male / Q000493:pharmacokinetics / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics; D012669:Seminal Vesicles / Q000187:drug effects / Q000502:physiology; D012726:Sexual Behavior, Animal / Q000187:drug effects / Q000502:physiology; D013091:Spermatogenesis / Q000187:drug effects
chemical_list: D000728:Androgens; D000813:Anilides; D003272:Contraceptive Agents, Male; C538983:N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluoro-4-chlorophenoxy)-2-hydroxy-2-methylpropanamide; D011944:Receptors, Androgen; C074283:estradiol 3-benzoate; D004958:Estradiol
references.citation: Endocrinology. 2000 Aug;141(8):2779-85
references.pmid: 10919263
references.citation: Mol Pharmacol. 2003 Jan;63(1):211-23
references.pmid: 12488554
references.citation: J Med Chem. 2004 Feb 12;47(4):993-8
references.pmid: 14761201
references.citation: Pharm Res. 2007 Feb;24(2):328-35
references.pmid: 17063395
references.citation: N Engl J Med. 1997 Jul 10;337(2):91-5
references.pmid: 9211678
references.citation: Eur J Endocrinol. 1999 Jul;141(1):40-6
references.pmid: 10407221
references.citation: Biochem Biophys Res Commun. 1999 May 27;259(1):56-9
references.pmid: 10334915
references.citation: Fertil Steril. 1996 Apr;65(4):821-9
references.pmid: 8654646
references.citation: Nature. 1977 Sep 29;269(5627):409-11
references.pmid: 909588
references.citation: Biochem Biophys Res Commun. 1998 Mar 6;244(1):1-4
references.pmid: 9514878
references.citation: J Pharmacol Exp Ther. 2005 Oct;315(1):230-9
references.pmid: 15987833
references.citation: Nat Clin Pract Endocrinol Metab. 2006 Jan;2(1):32-41
references.pmid: 16932251
references.citation: Nature. 1970 Aug 29;227(5261):964-5
references.pmid: 5449005
references.citation: J Clin Endocrinol Metab. 2003 Feb;88(2):562-8
references.pmid: 12574181
references.citation: J Endocrinol. 1971 Oct;51(2):241-52
references.pmid: 5121829
references.citation: Endocrinology. 1989 Jun;124(6):3043-9
references.pmid: 2498065
references.citation: J Pharmacol Exp Ther. 2005 Feb;312(2):546-53
references.pmid: 15347734
references.citation: Lancet. 1990 Oct 20;336(8721):955-9
references.pmid: 1977002
references.citation: Endocrinology. 1992 Jun;130(6):3283-8
references.pmid: 1597140
references.citation: Biol Reprod. 2003 Apr;68(4):1299-307
references.pmid: 12606480
references.citation: Endocrinology. 1990 Jul;127(1):177-84
references.pmid: 2113863
references.citation: Biochim Biophys Acta. 1967 Apr 4;137(2):356-66
references.pmid: 6051566
references.citation: Endocrinology. 2005 Dec;146(12):5444-54
references.pmid: 16166218
references.citation: J Pharmacol Exp Ther. 2003 Mar;304(3):1334-40
references.pmid: 12604714
references.citation: Endocrinology. 2007 Jan;148(1):363-73
references.pmid: 17023534
references.citation: Endocrinology. 2004 Dec;145(12):5420-8
references.pmid: 15308613
references.citation: Trends Endocrinol Metab. 2006 Mar;17(2):55-64
references.pmid: 16480891
references.citation: J Clin Endocrinol Metab. 2002 Dec;87(12):5476-84
references.pmid: 12466340
references.citation: Mol Interv. 2005 Jun;5(3):173-88
references.pmid: 15994457
references.citation: Science. 1973 Oct 19;182(4109):283-5
references.pmid: 4742734
references.citation: J Urol. 1981 Jul;126(1):46-8
references.pmid: 6788960
references.citation: Ann N Y Acad Sci. 2005 Dec;1061:208-20
references.pmid: 16467270
references.citation: J Clin Endocrinol Metab. 1995 Dec;80(12):3689-98
references.pmid: 8530621
references.citation: Endocrinology. 1950 May;46(5):453-81
references.pmid: 15414821
references.citation: Acta Endocrinol (Copenh). 1974 Dec;77(4):636-42
references.pmid: 4479701
references.citation: Endocrinology. 1984 Nov;115(5):1925-32
references.pmid: 6541571
references.citation: J Clin Endocrinol Metab. 2004 Jan;89(1):61-70
references.pmid: 14715828
references.citation: Behav Biol. 1977 May;20(1):141-8
references.pmid: 869850
references.citation: J Androl. 1998 Nov-Dec;19(6):725-35
references.pmid: 9876024
references.citation: Invest Urol. 1973 Nov;11(3):190-3
references.pmid: 4749418
references.citation: Endocrinology. 1989 Sep;125(3):1303-9
references.pmid: 2667955
references.citation: Hum Reprod. 2000 Mar;15(3):672-9
references.pmid: 10686218
references.citation: Clin Endocrinol (Oxf). 1999 Oct;51(4):517-24
references.pmid: 10583321
references.citation: Endocr Rev. 2002 Dec;23(6):735-62
references.pmid: 12466187
references.citation: Eur J Endocrinol. 1999 May;140(5):468-73
references.pmid: 10229915
references.citation: Trends Pharmacol Sci. 2004 Jan;25(1):49-57
references.pmid: 14723979