Optimization of in vivo validated ADCY10 inhibitors

项目1 精子必须是能动的并完全获能才能使卵母细胞受精。可溶性腺苷酸环化酶 (sAC)是精子中的一种酶，对于这两个过程都至关重要。sAC敲除小鼠是雄性特异性的 不育，而具有破坏sAC的突变的男性不育。在小鼠和人中，所有其他表型 观察到需要长时间的sAC缺失才能显现。因此，急性作用的sAC抑制剂可以是 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引发 副作用仅见于sAC缺失数月或数年。这种男性避孕药只会 在性交前不久，根据需要随时服用。威尔康奈尔医学的目标是 避孕研究中心（WCM-CRC）将开发急性作用的sAC抑制剂， 避孕药该避孕开发研究项目的重点是推进体内 经验证的sAC抑制剂化学系列，证明了按需男性的概念验证 老鼠避孕该系列中的一种“工具”化合物使雄性小鼠暂时不育。在这 项目，我们建议铅优化，以提高药代动力学特性，同时保持（或 改善）效力、药物样性质和其它限定功效的特征。这些研究的目的是 一系列开发良好的、有效的、选择性的、药物样的、无毒的、口服可用的sAC抑制剂， 药代动力学特征，以进行体内动物试验（WCM-CRC项目2）。我们的最终 我们的目标是将优化的电极导线推进到适合FDA研究的临床开发候选产品中 新药（IND）申请，以测试一种新型的男性口服非激素避孕药。

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.