Development of new ADCY10 inhibitors

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Project 3 Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Both processes require soluble adenylyl cyclase (sAC). sAC knockout mice are male specific sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, there are no other immediate phenotypes; thus, an acutely acting sAC inhibitor which blocks sperm functions for hours would be an effective on-demand male contraceptive without eliciting mechanism-based side effects that only manifest when sAC is absent for months or years. Such a male birth control pill would be taken only 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. Project 1 of the WCM-CRC proposes lead optimization of a chemical series already validated in a preclinical animal model. In this Contraception Development Research Project, we propose to develop additional leads, starting from scaffolds structurally distinct from the series optimized in Project 1, into selective, potent, drug-like sAC inhibitors. We propose to leverage our proven workflow of structure-based drug design along with functional testing, to refine these novel chemical scaffolds into inhibitors with increased potency, selectivity, long residence times, and drug-like properties. The ultimate goal of this Project is to develop additional, structurally unrelated, sAC inhibitors as lead compounds to be subjected to the pipeline of refinement cycles and in vivo studies described in other projects of this WCM-CRC.