Development of new ADCY10 inhibitors

项目3 精子必须活动和完全获能才能使卵母细胞受精。这两个过程都需要 可溶性腺酰环化酶(SAC)。SAC基因敲除小鼠是男性特有的不育，而携带突变的男性 破坏SAC是不育的。在老鼠和人身上，都没有其他直接的表型；因此，急性 能阻止精子功能数小时的代理SAC抑制剂将是有效的按需男性 避孕药没有引起基于机制的副作用，只有在没有SAC的情况下才会出现 几个月或几年。这样的男性避孕药只有在需要的时候才会服用，而且会在短期内经常服用 在做爱之前。威尔康奈尔医学避孕研究中心的目标是 将作用强烈的SAC抑制剂开发成按需避孕药。WCM-CRC项目1 建议对已经在临床前动物模型中验证的一系列化学物质进行铅优化。在这 避孕发展研究项目，我们建议开发更多的线索，从 支架的结构与项目1中优化的系列不同，成为选择性的、有效的、类药物的SAC 抑制剂。我们建议利用我们成熟的基于结构的药物设计工作流程，以及 功能测试，将这些新的化学支架提炼成具有更高效力，选择性， 较长的停留时间，以及类似毒品的特性。这个项目的最终目标是开发更多的， 结构上无关，SAC抑制剂作为先导化合物将受到精炼管道的影响 WCM-CRC的其他项目中描述的周期和体内研究。

Project 3 Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Both processes require soluble adenylyl cyclase (sAC). sAC knockout mice are male specific sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, there are no other immediate phenotypes; thus, an acutely acting sAC inhibitor which blocks sperm functions for hours would be an effective on-demand male contraceptive without eliciting mechanism-based side effects that only manifest when sAC is absent for months or years. Such a male birth control pill would be taken only 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. Project 1 of the WCM-CRC proposes lead optimization of a chemical series already validated in a preclinical animal model. In this Contraception Development Research Project, we propose to develop additional leads, starting from scaffolds structurally distinct from the series optimized in Project 1, into selective, potent, drug-like sAC inhibitors. We propose to leverage our proven workflow of structure-based drug design along with functional testing, to refine these novel chemical scaffolds into inhibitors with increased potency, selectivity, long residence times, and drug-like properties. The ultimate goal of this Project is to develop additional, structurally unrelated, sAC inhibitors as lead compounds to be subjected to the pipeline of refinement cycles and in vivo studies described in other projects of this WCM-CRC.