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

H2-甘孟唑类似物作为可逆非激素男性避孕药

• 批准号: 8889699
• 负责人: JOSEPH S TASH
• 金额: $ 25.54万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889699
• 关键词: Actins; Address; Adult; Adverse effects; Apical; Behavior; Binding; Binding Sites; Bioavailable; Biological Assay; Biological Availability; Biological Markers; Blood; Budgets; Bundling; Cells; Chemicals; Clinical Trials; Contraceptive Agents; Data; Decision Making; Development; Dose; Drug Kinetics; Ensure; Environment; F-Actin; Family Planning; Fertility; Funding; Goals; Health; Human; In Vitro; Infertility; Instruction; Link; Macaca mulatta; Male Contraceptive Agents; Monitor; Oral; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Post-Translational Protein Processing; Pregnancy; Process; Proteins; Protocols documentation; Rattus; Recovery; Resources; Rest; Safety; Seminal fluid; Signal Pathway; Signal Transduction; Signaling Protein; Site; Sperm Count Procedure; Spermatids; Spermiogenesis; Structural Protein; Testicular Hormones; Testing; Toxicology; United States National Institutes of Health; Woman; Work; analog; base; clinical toxicology; contraceptive target; design; high throughput screening; in vivo; inhibitor/antagonist; light scattering; male; mating behavior; men; mutant; nonhuman primate; novel; pre-clinical; premature; programs; protein protein interaction; protein structure; reproductive; research and development; scaffold; sertoli cell; small molecule; src-Family Kinases; success; three dimensional structure; uptake; virtual

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.

在上一个U54的资金期间，我们专注于开发一类新型SNNALL分子口服非激素 抗渗透性避孕药。其中，现在确定了H2-Gamendazole（H2-GMZ） 最有前途的 大鼠，交配行为没有损失。非人类灵长类动物的试验概念证明研究表明 可逆的精子计数和精液精子数量下降，没有不利的副作用。 H2-gmz 被Sertoli细胞迅速吸收，似乎通过结合和 与顶端外质专长相关的EEF1A-F-肌动蛋白束的破坏。另一种 化合物，纳尔西斯汀（NAR），也已被鉴定 Sertoli细胞中的典型EEF1A-肌动蛋白捆绑功能。为了实现移动H2的总体目标 GMZ朝着FDA IND状态和临床试验，非人类灵长类动物的关键疗效数据，详细阐述了所有 H2-GMZ作用机理的步骤以及审慎发现替代化学铅的步骤是 需要。因此，该项目的总体假设是H2-GMZ和其他小分子 可逆地破坏Sertoli细胞中的Eefia-Actin捆绑可以作为临床上有用的可逆 抗渗透性避孕药。提出了三个具体目标来实现这些目标： AIM 1：确定口服低剂量H2-GMZ的概念证明功效和药代动力学作为可逆 非人类灵长类动物中的抗渗透性避孕剂。 AIM 2：确定H2-GI \/Iz的机制和新型的小分子引诱的EEF1A actinbundling的变化 以及对精子过早损失的翻译后修改。 AIM 3：确定并优化其他新型的选择性小分子，以模仿H2-GMZ-EEF1A作用为抗 精子避孕药。 在这些努力中的成功将提供所需的基本数据，以使最终将H2-GMZ转移到 临床前毒理学和注册是人类临床试验的FDA IND。