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: 9127311
• 负责人: Vargheese Mani Chennathukuzhi
• 金额: $ 25.94万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127311
• 关键词: Actins; Address; Adult; Adverse effects; Apical; Binding; Binding Sites; Bioavailable; Biological Assay; Biological Availability; Blood; Budgets; Bundling; Chemicals; Clinical Trials; Collaborations; Contraceptive Agents; Data; Decision Making; Development; Dose; Drug Kinetics; Ensure; Environment; F-Actin; Family Planning; Fertility; Funding; Goals; Health; Human; In Vitro; Infertility; Instruction; Laboratories; Link; Macaca mulatta; Male Contraceptive Agents; Monitor; Oral; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Post-Translational Protein Processing; Pregnancy; Process; Production; Proteins; Protocols documentation; Rattus; Recovery; Resources; Rest; Safety; Seminal fluid; Signal Pathway; Signal Transduction; Signaling Protein; Site; Sperm Count Procedure; Spermatids; Spermiogenesis; Structural Genes; 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; potential biomarker; 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.

在之前的U54资助期间，我们重点开发了一类新型snnall分子口服非激素药物 抗生精避孕药。其中，现已鉴定出 H2-加孟唑 (H2-GMZ) 作为最有前途的，口服生物利用度为 100%，并且 100% 不育，随后 100% 恢复生育能力 大鼠，交配行为没有丧失。在非人类灵长类动物中进行的试点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下降，且无不良副作用。 H2-GMZ 被支持细胞迅速吸收，并似乎通过结合和导致精子细胞过早释放 与顶端外质特化相关的 eEF1A-F-肌动蛋白束的破坏。另一种选择 化合物水仙环素 (NAR) 也被发现对非 支持细胞中典型的 eEF1A-肌动蛋白捆绑功能。为了实现移动H2的总体目标 GMZ 针对 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 作用机制的步骤以及替代化学先导物的审慎发现是 需要。因此，该项目的总体假设是 H2-GMZ 和其他小分子 可逆性破坏支持细胞中的 eEFIA-肌动蛋白成束，可开发为临床上有用的可逆性 抗生精避孕药。为了实现这些目标，提出了三个具体目标： 目标 1：确定口服低剂量 H2-GMZ 作为可逆药物的概念验证功效和药代动力学 非人类灵长类动物的抗生精避孕剂。 目标 2：确定 H2-GI\/IZ 和新型小分子引起的 eEF1A 肌动蛋白成束变化的机制 以及翻译后修饰对精子细胞过早丧失的影响。 目标 3：识别并优化其他模仿 H2-GMZ-eEF1A 作用的新型选择性小分子，作为抗 生精避孕药。 这些努力的成功将为最终将 H2-GMZ 转移到 临床前毒理学和 FDA IND 注册，以启动人体临床试验。

项目成果

Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.

开发高效且选择性的细胞周期蛋白依赖性激酶二氨基噻唑抑制剂。

• DOI: 10.1021/jm301234k
• 发表时间: 2013-05-23
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Schonbrunn, Ernst;Betzi, Stephane;Alam, Riazul;Martin, Mathew P.;Becker, Andreas;Han, Huijong;Francis, Rawle;Chakrasali, Ramappa;Jakkaraj, Sudhakar;Kazi, Aslamuzzaman;Sebti, Said M.;Cubitt, Christopher L.;Gebhard, Anthony W.;Hazlehurst, Lori A.;Tash, Joseph S.;Georg, Gunda I.
• 通讯作者: Georg, Gunda I.