On-Demand Pharmacological Contraception by Blocking ADCY 10

总括 新鲜射出的哺乳动物精子不能使卵子受精。他们获得了受精 射精后数小时内通过女性生殖道的能力 这一过程被称为获能。可溶性腺酰环化酶(SAC：ADCY10)是一种非激素性物质 靶标对精子获能和男性生育能力至关重要。药物性SAC抑制剂阻断 精子的体外功能和两个不同的SAC基因敲除(KO)小鼠品系表现出男性特异性 不育而不表现出其他明显的表型。这个拟建的避孕研究中心 (儿童权利公约)有一个独特的科学主题；找出最安全和最有效的方法 在体内阻断SAC以实现按需避孕药。中国铁路公司的总体设计 利用已经成功的跨学科团队，该团队由SAC的专业知识组成 药理学和生物化学(Levin和Buck博士)，SAC结构生物学(Steegborne博士)，以及 药物化学和药物开发[Meinke博士和他的团队在三所 治疗药物发现研究所(TDI)]。为了完成CRC，我们为这个团队增加了一名男科医生 CORE(由兰姆和施莱格尔博士领导)，用于评估对人类精子的疗效。在前两个 项目中，我们将重点放在SAC催化结构域抑制剂上，期望药物动力学 可以对参数进行优化，以平衡疗效和最小的副作用。在第一个项目中， 我们将进行有效性、安全性和药代动力学的体内研究，以完善现有的 在小鼠中证实有效的SAC抑制剂支架成为临床前开发候选药物 适用于开发合作伙伴申请FDA研究新药(IND)。目标是 项目2的基础是在重组和优化部分的基础上开发更多的线索 从不同的，但结构和生物化学验证的支架，这将适合于 受制于项目1中提出的活体研究。第三个项目提出了一个高 以SAC异构体调节结构域为靶点的通过量筛选策略 富含精子。这样的抑制剂应该表现出减少的副作用。的最终目标是 项目3是确定将使用概述的相同原则和方法开发的HITS 在项目1和2中。在这项CRC中检验的总体假设是SAC抑制剂可以 设计成可以适当地剂量来阻止精子功能，同时将不受欢迎的情况降到最低 副作用。

Overall Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing capacity in the hours following ejaculation, as they pass through the female reproductive tract, in a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific sterility without exhibiting other overt phenotypes. This proposed Contraception Research Center (CRC) has a singular scientific theme; to identify the safest and most efficacious means for blocking sAC in vivo to achieve an on-demand contraceptive pill. The overall design of the CRC leverages the already successful interdisciplinary team comprised of expertise in sAC pharmacology and biochemistry (Drs. Levin & Buck), sAC structural biology (Dr. Steegborn), and medicinal chemistry and drug development [Dr. Meinke & his team at the Tri-Institutional Therapeutics Discovery Institute (TDI)]. To complete the CRC, we add to this team an Andrology Core (led by Drs. Lamb & Schlegel) for assessing efficacy against human sperm. In the first two Projects, we focus on sAC catalytic domain inhibitors with the expectation that pharmacokinetic parameters can be optimized to balance efficacy with minimal adverse effects. In the first project, we will perform in vivo studies of efficacy, safety, and pharmacokinetics to refine the existing scaffold of sAC inhibitors with proven efficacy in mice into preclinical development candidates suitable for development partners to apply for an FDA Investigational New Drug (IND). The goal of Project 2 is to develop additional leads, based upon recombination and optimization of moieties from distinct, but structurally and biochemically validated scaffolds, which would be suitable for subjecting to the in vivo studies proposed in Project 1. The third project proposes a high throughput screening strategy to identify inhibitors targeting regulatory domains of sAC isoforms enriched in sperm. Such inhibitors should exhibit diminished side effects. The ultimate goal of Project 3 is to identify hits which will be developed using the same principles and methods outlined in Projects 1 and 2. The overall hypothesis tested in this CRC is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects.