Shi Rui, Wolgemuth Debra J, Georg Gunda I
Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States.
Department of Genetics and Development, Columbia University Medical Center, New York, NY, United States; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY, United States; The Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, United States; The Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, United States.
Contraception. 2025 May;145:110809. doi: 10.1016/j.contraception.2024.110809. Epub 2025 Jan 3.
Genetic studies in mice have demonstrated that retinoic acid receptor alpha (RARα) deficiency leads to male infertility without affecting overall viability, suggesting that pharmacological inhibition of this receptor could be a viable contraceptive strategy. This review describes the use of experimental approaches to develop RARα-selective antagonists for male contraception. Initial studies with BMS-189453, a pan-RAR antagonist, showed significant testicular degeneration and reversible infertility in mice. The search for RARα-specific antagonists led to the development of YCT-529, a potent and selective RARα antagonist with favorable pharmacokinetics. YCT-529 demonstrated excellent in vivo efficacy in inhibiting spermatogenesis and inducing infertility in mice, with fertility recovery following drug discontinuation. YCT-529 is now in clinical development as a candidate for male contraception.
对小鼠的遗传学研究表明，维甲酸受体α（RARα）缺乏会导致雄性不育，但不影响整体生存能力，这表明对该受体进行药理学抑制可能是一种可行的避孕策略。这篇综述描述了使用实验方法开发用于男性避孕的RARα选择性拮抗剂。对泛RAR拮抗剂BMS-189453的初步研究表明，小鼠出现了明显的睾丸退化和可逆性不育。对RARα特异性拮抗剂的探索导致了YCT-529的开发，这是一种具有良好药代动力学的强效且选择性的RARα拮抗剂。YCT-529在抑制小鼠精子发生和诱导不育方面表现出优异的体内疗效，停药后生育能力可恢复。YCT-529目前正处于作为男性避孕候选药物的临床开发阶段。
