ALDH1A1/A2 Inhibitors for Male Contraception

用于男性避孕的 ALDH1A1/A2 抑制剂

• 批准号: 10020794
• 负责人: John K. Amory
• 金额: $ 38.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020794
• 关键词: Affect; Alcohols; Anabolism; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Biological Availability; C57BL/6 Mouse; Caco-2 Cells; Calorimetry; Cell Culture Techniques; Cells; Characteristics; Chemicals; Computers; Contraceptive Agents; Crystallization; Cysteine; Development; Disulfiram; Dreams; Enzymes; Ethanol Metabolism; Excretory function; Fertility; Fruit; Germ Cells; Goals; Half-Life; Hormones; Human; In Vitro; Isoenzymes; Lead; Liver; Liver Microsomes; Male Contraceptive Agents; Metabolic; Metabolism; Modeling; Modification; Molecular; Mus; Oral; Oral Administration; Pharmacologic Substance; Pharmacology; Piperazines; Placebos; Plasma; Plasma Proteins; Property; Pyrazoles; Reaction; Research Support; Roentgen Rays; Solubility; Specificity; Spermatids; Spermatogenesis; Structure; Testing; Testis; Testosterone; Titrations; Tretinoin; Work; absorption; aldehyde dehydrogenases; base; chemical synthesis; experimental study; improved; in vitro testing; in vivo; inhibitor/antagonist; male; man; men; novel; pharmacokinetics and pharmacodynamics; pill; prevent; reversible contraceptive; scaffold; side effect

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.

双二氯乙酰二胺（例如 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生物合成以及随后的精子发生。视黄酸是 由醛脱氢酶 1A1 和 1A2 (ALDH1A1/1A2) 在生殖细胞中产生，它们是 被 WIN 18,446 有效抑制。不幸的是，WIN 18,446 也抑制乙醛脱氢酶 2，导致 当 WIN 18,446 与酒精结合使用时，会发生双硫仑反应。在本提案中，我们将 开发新型特异性 ALDH1A1/1A2 抑制剂，无需抑制即可发挥避孕作用 乙醛脱氢酶2。我们开发了几种有效且特异性的 ALDH1A1/1A2 抑制剂，并对其进行了测试 广泛在体外和体内。目前的两种先导支架对 ALDH1A1/1A2 具有选择性，IC50 为 <200 nM 并且不抑制 ALDH2。然而，它们目前在抑制方面不如 BDAD 有效。 由于药物特性次佳而导致精子发生。在本提案的目标#1中，我们将优化 使用计算机引导确定我们抑制剂的效力、选择性、溶解度和药物特性 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 位于 ALDH1A 底物结合位点。在目标 2 中，我们将进行体外测试（溶解度、吸收度和 代谢）和体内药代动力学和药效学研究，以确定最佳抑制剂 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 抑制小鼠精子发生和生育力的抑制剂。如果成功的话，所提出的实验将产生 用于男性避孕的新型 ALDH1A1/1A2 特异性抑制剂，并导致一种有效的、口服的、非激素的 男性避孕药，终于圆了“男性避孕药”的梦想。