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
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
复制标题
DOI：
10.1210/en.2008-0674
复制
发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Dalton, James T.
中科院分区：
文献类型：
--
作者：
Jones, Amanda;Chen, Jiyun;Dalton, James T.
在雄性大鼠中表征了（S）-N-（4-氰基-3-三氟甲基-苯基）-3-（3-氟，4-氯苯氧基）-2-羟基-2-甲基-丙酰胺（S-23）的药理学作用，作为激素雄性避孕的动物模型。S-23显示出高结合亲和力（抑制常数= 1.7 +/- 0.2 nM），并在体外被鉴定为完全激动剂。在去势雄性大鼠中，S-23在前列腺和提肛肌中的ED 50分别为0.43和0.079 mg/d。在给药14天的完整雄性大鼠中，剂量大于0.1 mg/d时，S-23单独给药可抑制LH水平超过50%，前列腺大小相应减小，但提肛肌大小增加。在接受S-23和苯甲酸雌二醇（EB;维持大鼠性行为所必需）处理长达10周的完整雄性大鼠中，S-23通过抑制血清LH和FSH浓度对雄激素组织和精子发生显示出双相效应。EB单独对精子发生无影响。在EB + S-23（0.1 mg/d）组中，6只动物中有4只在交配试验中显示睾丸中无精子，0例妊娠（6只均未妊娠）。治疗结束后，不孕症是完全可逆的，在恢复100天后观察到100%的妊娠率。S-23以剂量依赖性方式增加骨密度和瘦体重，但减少脂肪量。这是第一项研究表明，选择性雄激素受体调节剂联合EB是一种有效的和可逆的方案，用于大鼠激素男性避孕。S-23对肌肉的有益作用、组织选择性和有利的药代动力学特性使其成为口服男性避孕药的强有力候选药物。（内分泌学150：385-395，2009）
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. (Endocrinology 150: 385-395, 2009)