ALDH1A1/A2 Inhibitors for Male Contraception

双二氯乙酰二胺如WIN 18，446可用作口服、可逆、非激素男性避孕药 通过抑制睾丸视黄酸的生物合成和随后的精子生成。视黄酸是 在生殖细胞中由醛脱氢酶-1A1和1A 2（ALDH 1A 1/1A 2）产生， 被WIN 18446强力抑制不幸的是，WIN 18，446也抑制醛脱氢酶-2，导致 当WIN 18，446与酒精联合给药时，双硫仑反应。在本提案中，我们将 开发新的ALDH 1A 1/1A 2特异性抑制剂，其可以发挥避孕作用而不抑制 ALDH 2.我们已经开发了几种有效和特异性的ALDH 1A 1/1A 2抑制剂，并对其进行了测试。 广泛地在体外和体内。目前的两种电极导线支架对ALDH 1A 1/1A 2具有选择性，IC 50为 <200 nM且不抑制ALDH 2。然而，它们目前在抑制 由于次优的药物特性而导致精子发生。在本提案的目标#1中，我们将优化 我们的抑制剂的效力，选择性，溶解度和药物特性，使用计算机引导 基于我们最近解决的抑制剂的X射线共晶结构的化学修饰 ALDH 1A底物结合位点。在目标#2中，我们将进行体外测试（溶解度、吸收和 代谢）和体内药代动力学和药效学研究，以确定最佳的抑制剂， 作为男性避孕药进行测试。在本提案的目标#3中，我们将测试最有前途的人的能力。 抑制剂，以抑制小鼠的精子发生和生育能力。如果成功的话，所提议的实验将导致 用于男性避孕新型ALDH 1A 1/1A 2特异性抑制剂，并导致有效的口服非激素 男性避孕药，终于实现了“男性避孕药”的梦想。

Bisdichloroacetyldiamines such as WIN 18,446 function as oral, reversible, non-hormonal male contraceptives by inhibiting testicular retinoic acid biosynthesis and, subsequently, spermatogenesis. Retinoic acid is produced in the germ cells by the enzymes aldehyde dehydrogenase-1A1 and 1A2 (ALDH1A1/1A2), which are potently inhibited by WIN 18,446. Unfortunately, WIN 18,446 also inhibits aldehyde dehydrogenase-2, leading to disulfiram reactions when administration of WIN 18,446 is combined with alcohol. In this proposal, we will develop novel specific inhibitors of ALDH1A1/1A2 that can exert contraceptive effects without inhibiting ALDH2. We have developed several potent and specific inhibitors of ALDH1A1/1A2, and tested them extensively in vitro and in vivo. The two current lead scaffolds are selective for ALDH1A1/1A2 with IC50s of <200 nM and do not inhibit ALDH2. However, they are currently not as effective as BDADs at suppressing spermatogenesis due to sub-optimal pharmaceutical properties. In Aims #1 of this proposal, we will optimize the potency, selectivity, solubility and pharmaceutical characteristics of our inhibitors using computer-guided chemical modifications based upon the our recently solved X-ray co-crystallographic structure of the inhibitors in the ALDH1A substrate binding site. In Aim #2 we will conduct in vitro testing (solubility, absorption and metabolism) and in vivo pharmacokinetic and pharmacodynamic studies to determine the best inhibitor for testing as a male contraceptive. In Aim #3 of this proposal, we will test the ability of the most promising inhibitors to suppress spermatogenesis and fertility in mice. If successful, the proposed experiments will result in novel specific inhibitors of ALDH1A1/1A2 for male contraception and lead to an effective, oral, non-hormonal male contraceptive, finally bringing the dream of a “male pill” to fruition.