Catsper Inhibitors for Male Contraception

PROJECT SUMMARY Male contraception has remained a long-desired, but yet to be met goal. Critical to this goal is the identification of a suitable and druggable target, and the availability of adequate compounds. The voltage-gated ion channel CatSper is an exceptionally promising target for male contraception because it is exclusively expressed in sperm, is critical for sperm function, and is required for male fertility. Mice in which CatSper has been genetically deleted are completely infertile. Furthermore, naturally occurring CatSper mutations have been identified as the cause of male factor infertility in humans. Hits from a high throughput screening (HTS) campaign, blocked high potassium, high pH- and progesterone induced Ca2+ influx into human sperm. Moreover, these compounds inhibited cell hyperpolarization and hyperactivated motility (HAM) of human sperm. An ion channel selectivity screening indicated good selectivity of some hits for CatSper over other ion channels. Based on these data, we hypothesize that we can discover and develop orally bioavailable highly selective Catsper inhibitors. The inhibitors will be characterized for inhibition of calcium influx, sperm motility, ion channel selectivity, and in vitro ADMET assays. Promising compounds will be investigated for pharmacokinetic properties before examining their effectiveness on reduction of sperm motility and HAM, reversibility in mice and on mating trials in mice. We will also monitor off-target effects and determine preliminary maximum tolerated doses. The goal for this project is the development of a preclinical candidate for male contraception.