Development of Inhibitors For the Cation Channels of Sperm For Male Contraception

Abstract

Currently, there is an unmet need for selective, non-hormonal male contraceptive agents. The cation channels of sperm (CatSper) are sperm-specific, voltage-gated ion channels that regulate the internal calcium (Ca2+) concentration in mature spermatozoa. These channels are activated by the alkaline environment of the female reproductive tract, resulting in an influx of Ca2+ initiating hyperactivated motility (HAM) necessary for fertilization. Mutations within CatSper, as confirmed by mouse knockout studies, lead to infertility in males with no other observable phenotypes, validating CatSper as a target for male contraception. We envision that the development of CatSper inhibitors will serve as a selective, reversible, and non-hormonal means to male contraception. A 70,000 compound high-throughput screening campaign was performed, using human sperm and a Fluorescent Imaging Plate Reader (FLIPR) assay to measure Ca2+ influx yielded seven hits with micromolar potencies. Two of these hits, compounds 1 and 2, were confirmed by electrophysiology as CatSper inhibitors and selected for structure-activity relationship studies. This thesis reports on the design, synthesis, and testing of analogs related to these two hits.