Optimization of lead candidates for an on-demand male contraceptive

哺乳动物的精子以休眠状态储存在附睾中;它们是不动的， 让卵子受精射精后，精子开始游动，并启动一个称为 获能，使它们有能力施肥。获能的初始事件， 运动性的激活是HCO 3诱导的可溶性腺苷酸环化酶（sAC：ADCY 10）的刺激。 sAC基因敲除的男性和雄性小鼠不育， 特异于sAC阻断体外受精并暂时使雄性小鼠不育。因此，sAC是 一种基因和经验证的非激素靶点，对男性生育力至关重要。的 在本申请中测试的总体假设是可以设计sAC抑制剂， 适当剂量以阻断精子功能，同时最小化不良副作用。我们 建议使用体外和体内研究测试一系列有效的选择性sAC抑制剂， 有效性、安全性和药代动力学，以确定最成熟、有效、选择性， 类药物、无毒的sAC抑制剂。该项目的目标是从这个推进化合物 适合开发合作伙伴申请的临床前开发候选产品系列 FDA研究新药（IND），用于新型口服非激素避孕药。

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.