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

Amanda Jones, Jiyun Chen, Dong Jin Hwang, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

33 Citations (Scopus)

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. Aftertermination 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.

Original languageEnglish (US)
Pages (from-to)385-395
Number of pages11
JournalEndocrinology
Volume150
Issue number1
DOIs
StatePublished - Jan 1 2009

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1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
Androgen Receptors
Contraception
Anal Canal
Spermatogenesis
Muscles
Prostate
2-(4-chlorophenoxy)-2-methylpropanamide
Pregnancy Rate
Sexual Behavior
Bone Density
Infertility
Spermatozoa
Testis
Animal Models
Pharmacokinetics

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

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. / Jones, Amanda; Chen, Jiyun; Hwang, Dong Jin; Miller, Duane; Dalton, James T.

In: Endocrinology, Vol. 150, No. 1, 01.01.2009, p. 385-395.

Research output: Contribution to journalArticle

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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. Aftertermination 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.",
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