Optimization of in vivo validated ADCY10 inhibitors

项目1 精子必须活动和完全获能才能使卵母细胞受精。可溶性腺酰环化酶 (SAC)是精子中的一种酶，对这两个过程都是必不可少的。SAC基因敲除小鼠是雄性特有的 不育，而带有破坏SAC的突变的男性是不育的。在老鼠和人类中，所有其他表型 观察到需要长时间的SAC消失才能显现。因此，一种作用强烈的SAC抑制剂可能是 一种安全有效的按需避孕药，通过阻断精子功能数小时而不会引发 副作用只有在SAC几个月或几年没有出现时才会出现。这样的男性避孕药只会 在性交前不久，根据需要随时服用。威尔·康奈尔医学的目标 避孕研究中心(WCM-CRC)将根据需要开发出有效的SAC抑制剂 避孕药。这项避孕开发研究项目致力于在体内推进 经过验证的SAC抑制剂化学系列，为按需男性提供了概念验证 在小鼠身上避孕。这一系列中的一种“工具”化合物使雄性小鼠暂时不育。在这 项目中，我们建议优化Lead以增强药代动力学特性，同时保持(或 改进)效力、类药物特性和其他功效定义特征。这些研究的目标是 一系列开发成熟、有效、选择性、类药物、无毒、口服可用的SAC抑制剂，具有更好的 进入活体动物试验的药代动力学曲线(WCM-CRC项目2)。我们的终极 目标是将优化的线索推进到适合FDA调查的临床开发候选对象 新药(IND)申请测试一种用于男性的新型口服非激素避孕药。

Project 1 Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Soluble adenylyl cyclase (sAC) is an enzyme in sperm that is essential for both processes. sAC knockout mice are male specific sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, all other phenotypes observed require long periods of sAC absence to manifest. Thus, an acutely acting sAC inhibitor could be a safe and effective on-demand contraceptive by blocking sperm functions for hours without eliciting the side effects only seen when sAC is absent for months or years. Such a male birth control pill would only be taken when, and as often, as needed, shortly before sex. The goal of the Weill Cornell Medicine Contraception Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand birth control pills. This Contraception Development Research Project focuses on advancing the in vivo validated chemical series of sAC inhibitors which demonstrated proof-of-concept for on-demand male contraception in mice. A `tool' compound from this series renders male mice temporarily infertile. In this project, we propose lead optimization to enhance pharmacokinetic properties while maintaining (or improving) potency, drug-like properties, and other efficacy-defining features. The goal of these studies is a series of well-developed, potent, selective, drug-like, non-toxic, orally available sAC inhibitors with better pharmacokinetic profiles to progress into in vivo animal testing (Project 2 of the WCM-CRC). Our ultimate goal is to advance optimized leads into clinical development candidates suitable for an FDA Investigational New Drug (IND) application to test a novel oral, nonhormonal contraceptive for men.