Optimization of lead candidates for an on-demand male contraceptive

哺乳动物的精子储存在附睾处，处于休眠状态；它们是不活动的，不能 使卵子受精。在射精时，精子开始游动，并启动一个称为 获能，在那里它们变得有能力受精。获能和获能的初始事件 运动的激活是由HCO3诱导的对可溶性腺苷环化酶(SAC：ADCY10)的刺激。 带有SAC基因敲除的男性和雄性小鼠是不育的，药物抑制剂 特异性为SAC阻断体外受精，暂时使雄性小鼠不育。因此，SAC是 一种经过遗传和药物验证的非荷尔蒙靶标，对男性生育能力至关重要。这个 在本申请中检验的总体假设是，SAC抑制剂可以设计成 适当的剂量，以阻止精子功能，同时最大限度地减少不良副作用。我们 建议测试一系列有效的、选择性的SAC抑制剂，使用体外和体内研究 有效性、安全性和药代动力学，以确定最成熟、最有效、最有选择性的 类药物，无毒的SAC抑制剂。该项目的目标是在此基础上开发一种化合物 适合开发合作伙伴申请的临床前开发候选人系列 FDA研究新药(IND)，用于一种新型的口服非激素避孕药。

Mammalian sperm are stored in the epididymis in a dormant state; they are immotile and unable to fertilize the egg. Upon ejaculation, sperm begin swimming and initiate a process called capacitation, where they become competent to fertilize. An initial event in capacitation and activation of motility is the HCO3- induced stimulation of soluble adenylyl cyclase (sAC: ADCY10). Men and male mice with the sAC gene knocked out are infertile, and pharmacological inhibitors specific for sAC block in vitro fertilization and temporarily render male mice infertile. Thus, sAC is a genetic and pharmacologically validated, non-hormonal target essential for male fertility. The overall hypothesis tested in this application is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. We propose to test a series of potent, selective sAC inhibitors, using in vitro and in vivo studies of efficacy, safety, and pharmacokinetics, to identify the most well-developed, potent, selective, drug-like, non-toxic sAC inhibitors. The goal of this Project is to advance a compound from this series into preclinical development candidates suitable for development partners to apply for an FDA Investigational New Drug (IND) for a novel oral, non-hormonal contraceptive.