Chung Sanny S W, Cuellar Rebecca A D, Wang Xiangyuan, Reczek Peter R, Georg Gunda I, Wolgemuth Debra J
Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032.
ACS Med Chem Lett. 2013 May 9;4(5):446-450. doi: 10.1021/ml300365k.
Oral administration of a retinoic acid receptor (RAR) pan-antagonist reversibly inhibits spermatogenesis. Given the importance of RARα in regulating spermatogenesis, we identified two RARα-selective antagonists by transactivation and transactivation competition assays and asked whether they effectively inhibit spermatogenesis. Although these two antagonists were potent , they displayed poor activity in mice when administered orally. Testicular weights were normal and morphological analysis revealed normal spermatid alignment and sperm release. drug property analyses were performed with one of these antagonists and compared with the pan-antagonist. We showed that the discrepancies may be explained by several factors, including high plasma protein binding, faster hepatic metabolism relative to the pan-antagonist, and only moderate permeability. The conclusion of poor oral bioavailability was supported by more pronounced defects in mice when the antagonist was administered intravenously versus intraperitoneally. These results are crucial for designing new RARα-selective antagonists for pharmaceutical application.
口服视黄酸受体（RAR）泛拮抗剂可可逆地抑制精子发生。鉴于RARα在调节精子发生中的重要性，我们通过反式激活和反式激活竞争试验鉴定了两种RARα选择性拮抗剂，并研究它们是否能有效抑制精子发生。尽管这两种拮抗剂效力很强，但口服给药时在小鼠体内活性不佳。睾丸重量正常，形态学分析显示精子细胞排列和精子释放正常。我们对其中一种拮抗剂进行了药物性质分析，并与泛拮抗剂进行了比较。我们发现，这些差异可能由几个因素解释，包括高血浆蛋白结合率、相对于泛拮抗剂更快的肝脏代谢以及仅中等的通透性。当静脉注射与腹腔注射该拮抗剂时，小鼠出现更明显的缺陷，这支持了口服生物利用度差的结论。这些结果对于设计用于药物应用的新型RARα选择性拮抗剂至关重要。
