Assessing inhibitor efficacy in vivo and developing a biomarker for use during early phase clinical trials

计划2 哺乳动物的精子以休眠状态储存在附睾中;它们是不动的，不能受精 卵母细胞射精后，运动性通过碳酸氢盐诱导的可溶性腺苷酸刺激而激活 环化酶（sAC：ADCY 10）。sAC基因敲除的男性和雄性小鼠是不育的， sAC特异性药理学抑制剂阻断体外受精并使雄性小鼠暂时 不能生育因此，sAC是一个非激素靶点，在遗传学和生物学上被证实是必需的 男性生育能力威尔康奈尔医学避孕研究中心（WCM-CRC）的目标是 将急性作用的sAC抑制剂开发成安全有效的非激素、口服、按需 避孕药，男性只在需要时和在性交前不久才服用。在这个避孕 转化研究项目，我们将建立第二个，非啮齿类动物模型进行测试 避孕功效;测试优化的sAC抑制剂的体内功效;并验证精子活力， 用于按需男性的早期临床试验的疗效的药效学生物标志物 避孕药该项目和WCM-CRC的目标是确定一名主要候选人（沿着 备份）进行研究，使研究性新药（IND）申请成为一种新型口服， 男性非激素避孕药。

Project 2 Mammalian sperm are stored in the epididymis in a dormant state; they are immotile and unable to fertilize the oocyte. Upon ejaculation, motility is activated via bicarbonate-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 render male mice temporarily infertile. Thus, sAC is a nonhormonal target, genetically and pharmacologically validated to be essential for male fertility. The goal of the Weill Cornell Medicine Contraceptive Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into safe and effective nonhormonal, orally available, on-demand contraceptives which men take only when and as often as needed, shortly before sex. In this Contraception Translational Research Project, we will establish a second, non-rodent animal model for testing contraceptive efficacy; test the in vivo efficacy of optimized sAC inhibitors; and validate sperm motility as a pharmacodynamic biomarker of efficacy for use in early phase clinical trials of an on-demand male contraceptive. A goal of this Project, and the WCM-CRC, is to identify a lead candidate (along with backups) to progress into studies enabling an Investigational New Drug (IND) application as a novel oral, nonhormonal contraceptive for men.