ALDH1A1/A2 Inhibitors for Male Contraception

双氯乙酰二胺，如Win 18,446，用作口服、可逆、非激素的男性避孕药 通过抑制睾丸维甲酸的生物合成，进而抑制精子发生。维甲酸是 在生殖细胞中由乙醛脱氢酶-1A1和1A2(ALDH1A1/1A2)酶产生，这两种酶是 被18,446的胜利有力地抑制了。不幸的是，Win 18,446也抑制乙醛脱氢酶-2，导致 当Win 18,446与酒精联合给药时发生双硫胺反应。在这项提案中，我们将 开发无抑制避孕作用的新型ALDH1A1/1A2特异性抑制剂 ALDH2。我们已经开发了几种有效和特异的ALDH1A1/1A2抑制剂，并对它们进行了测试 在体外和体内广泛存在。目前的两种铅支架对ALDH1A1/1A2具有选择性，IC50为 &lt；200 nm，不抑制ALDH2。然而，它们目前在抑制BDAD方面没有BDAD那么有效 由于药学性质不佳而导致的精子生成。在本提案的目标1中，我们将优化 使用计算机引导我们的缓蚀剂的效力、选择性、溶解性和药学特性 基于我们最近解决的缓蚀剂的X-射线共晶体结构的化学修饰 在ALDH1A底物结合部位。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 作为一种男性避孕药进行测试。在本提案的第三个目标中，我们将测试最有前途的 抑制小鼠精子发生和生育的抑制剂。如果成功，拟议中的实验将导致 在新型的ALDH1A1/1A2特异性抑制剂中，用于男性避孕并导致有效的、口服的、非激素的 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.