Overall 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 the oocyte. An initial event in capacitation and activation of motility is the bicarbonate-induced stimulation of soluble adenylyl cyclase (sAC: ADCY10). Men and male mice with the sAC gene knocked out are infertile, and in vivo administration of sAC inhibitors to male mice prevents sperm motility and renders the males temporarily infertile. Thus, sAC is a nonhormonal target, genetically and pharmacologically validated to be essential for male fertility. Besides male-specific sterility, the only other phenotypes of sAC knockout men or mice are dependent upon chronic loss of sAC for extended periods of time. We propose to leverage acutely acting inhibitors, whose effects will be transient, to avoid mechanism-based side effects and limit the inherent perils associated with chronic dosing. 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 two Contraceptive Development Research Projects, we propose to improve binding affinity, pharmacokinetics (including oral bioavailability), drug-like characteristics, and safety of sAC inhibitors with the expectation that pharmacokinetic parameters can be optimized to balance efficacy with minimal adverse effects. In Project 1, we focus on a chemical series validated in vivo in a preclinical animal model, and in Project 3, we propose to develop additional leads from structurally distinct scaffolds. In Project 2, 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 major goal of the WCM-CRC is to identify a clinical lead candidate (along with backups) to advance into Investigational New Drug (IND) enabling studies for a novel oral, nonhormonal contraceptive for men.