Development of new ADCY10 inhibitors

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Project 2 Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing capacity in the hours following ejaculation, as they pass through the female reproductive tract, in a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific sterility without exhibiting other overt phenotypes. The overall hypothesis tested in this Contraception Research Center (CRC) is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. In Project 1, we embark on in vivo studies of an already developed series of potent, selective sAC inhibitors. In this Contraception Development Research Project, we will develop additional leads, based upon distinct structurally and biochemically validated scaffolds. Specifically, we will (1) design new chemical series by fragment-based drug design (FBDD) and structure-based drug design (SBDD) using available co-crystal structures of sAC with various inhibitors; (2) synthesize and test small panels of derivatives of these new chemical structures; and (3) use medicinal chemistry and structural biology to refine the compounds into inhibitors with improved potency, selectivity, and drug-like properties. Suitable alternative sAC inhibitors will be subjected to the pipeline of refinement cycles and in vivo studies described in Project 1 of this CRC. The ultimate goal of this Project is to develop sAC inhibitors as lead compounds for oral, non-hormonal contraceptives.