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.
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.
Jones
Amanda
A
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, L. M. Parks Hall, Room 242, Columbus, Ohio 43210, USA.
Chen
Jiyun
J
Hwang
Dong Jin
DJ
Miller
Duane D
DD
Dalton
James T
JT
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
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
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