H2-Gamendazole analogues as reversible non-hormonal male contraceptive agents

在之前的U54资助期间，我们专注于开发一类新型的SNALL分子口服非激素 抗生精避孕药。在这些化合物中，H2-甘马唑(H2-GMZ)现已确定 最有希望的是，100%口服生物利用度，100%不孕症，然后100%恢复生育能力 老鼠，在交配行为上没有损失。对非人类灵长类动物的先导概念验证研究完全表明 精子细胞数量和精液精子数量可逆性下降，没有不良副作用。H2-GMZ 被支持细胞迅速吸收，并似乎通过与精子细胞结合和 与顶端胞质特化相关的eEF1A-F-肌动蛋白-束的破坏。另一种选择 化合物Naciclasine(NAR)也被发现对非 支持细胞中典型的eEF1A-肌动蛋白结合功能。为了实现移动H2的总体目标 GMZ针对FDA的IND状态和临床试验，非人类灵长类动物的关键疗效数据，阐述了所有 H2-GMZ的作用机制和谨慎发现替代化学先导的步骤如下 需要的。因此，这个项目的总体假设是H2-GMZ和其他小分子 可逆性破坏支持细胞中eEFIA-肌动蛋白结合可发展为临床有用的可逆性 抗生精避孕药。为实现这些目标提出了三个具体目标： 目的1：确定口服小剂量H2-GMZ可逆性的概念验证、疗效和药代动力学 非人灵长类抗精子避孕药。 目的2：确定H2-GI/IZ的作用机制及新的小分子诱导的eEF1a结合变化 以及对精子细胞过早丧失的翻译后修饰。 目标3：确定和优化其他模拟H2-GMZ-eEF1A作用的新型选择性小分子 生精避孕药。 这些努力的成功将提供必要的数据，使H2-GMZ最终能够进入 临床前毒理学和注册为FDA IND，开始在人体上进行临床试验。

In the previous U54 funding period, we focused on developing a class of novel snnall molecule oral nonhormonal anti-spermatogenic contraceptive agents. Of these, H2-gamendazole (H2-GMZ) is now identified as most promising, with 100% oral bioavailability, and 100% infertility followed by 100% recovery of fertility in rats, with no loss in mating behavior. Pilot proof-of-concept studies in non-human primates showed completely reversible declines in spermatid count and semen sperm count with no adverse side effects. H2-GMZ is rapidly absorbed by Sertoli cells and appears to cause premature release of spermatids via binding to and disruption of the eEF1A-F-actin-bundles associated with the apical ectoplasmic specializations. An alternative compound, narciclasine (NAR), has also been identified with similar disruptive effects on the non canonical eEF1A-actin bundling function in Sertoli cells. In order to achieve the overall goal of moving H2 GMZ towards FDA IND status and clinical trials, critical efficacy data in non-human primates, elaborate all of the steps in the mechanism of action of H2-GMZ, and prudent discovery of alternative chemical leads are needed. Thus, the overall hypothesis for this project is that H2-GMZ and other small molecules that reversibly disrupt eEFIA-actin bundling in Sertoli cells can be developed as clinically useful reversible anti-spermatogenic contraceptive agents. Three specific aims are proposed to achieve these goals: Aim 1: Determine proof-of concept efficacy and pharmacokinetics of oral low-dose H2-GMZ as a reversible anti-spermatogenic contraceptive agent in non-human primates. Aim 2: Determine the mechanism of H2-GI\/IZ and novel small molecule-elicited changes in eEF1A actinbundling and post-translational modification on premature loss of spermatids. Aim 3: Identify and optimize other novel selective small molecules that mimic H2-GMZ-eEF1A actions as anti- spermatogenic contraceptive agents. Success in these endeavors will provide essential data needed to enable ultimately moving H2-GMZ into pre-clinical toxicology and registration as an FDA IND for the start of clinical trials in humans.