Project 1 Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Soluble adenylyl cyclase (sAC) is an enzyme in sperm that is essential for both processes. sAC knockout mice are male specific sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, all other phenotypes observed require long periods of sAC absence to manifest. Thus, an acutely acting sAC inhibitor could be a safe and effective on-demand contraceptive by blocking sperm functions for hours without eliciting the side effects only seen when sAC is absent for months or years. Such a male birth control pill would only be taken when, and as often, as needed, shortly before sex. The goal of the Weill Cornell Medicine Contraception Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand birth control pills. This Contraception Development Research Project focuses on advancing the in vivo validated chemical series of sAC inhibitors which demonstrated proof-of-concept for on-demand male contraception in mice. A `tool' compound from this series renders male mice temporarily infertile. In this project, we propose lead optimization to enhance pharmacokinetic properties while maintaining (or improving) potency, drug-like properties, and other efficacy-defining features. The goal of these studies is a series of well-developed, potent, selective, drug-like, non-toxic, orally available sAC inhibitors with better pharmacokinetic profiles to progress into in vivo animal testing (Project 2 of the WCM-CRC). Our ultimate goal is to advance optimized leads into clinical development candidates suitable for an FDA Investigational New Drug (IND) application to test a novel oral, nonhormonal contraceptive for men.