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

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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.