H2-Gamendazole analogues as reversible non-hormonal male contraceptive agents

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In the previous U54 funding period, we focused on developing a class of novel snnall molecule oral nonhormonal anti-spermatogenic contraceptive agents. Of these, H2-gamendazole (H2-GMZ) is now identified as most promising, with 100% oral bioavailability, and 100% infertility followed by 100% recovery of fertility in rats, with no loss in mating behavior. Pilot proof-of-concept studies in non-human primates showed completely reversible declines in spermatid count and semen sperm count with no adverse side effects. H2-GMZ is rapidly absorbed by Sertoli cells and appears to cause premature release of spermatids via binding to and disruption of the eEF1A-F-actin-bundles associated with the apical ectoplasmic specializations. An alternative compound, narciclasine (NAR), has also been identified with similar disruptive effects on the non canonical eEF1A-actin bundling function in Sertoli cells. In order to achieve the overall goal of moving H2 GMZ towards FDA IND status and clinical trials, critical efficacy data in non-human primates, elaborate all of the steps in the mechanism of action of H2-GMZ, and prudent discovery of alternative chemical leads are needed. Thus, the overall hypothesis for this project is that H2-GMZ and other small molecules that reversibly disrupt eEFIA-actin bundling in Sertoli cells can be developed as clinically useful reversible anti-spermatogenic contraceptive agents. Three specific aims are proposed to achieve these goals: Aim 1: Determine proof-of concept efficacy and pharmacokinetics of oral low-dose H2-GMZ as a reversible anti-spermatogenic contraceptive agent in non-human primates. Aim 2: Determine the mechanism of H2-GI\/IZ and novel small molecule-elicited changes in eEF1A actinbundling and post-translational modification on premature loss of spermatids. Aim 3: Identify and optimize other novel selective small molecules that mimic H2-GMZ-eEF1A actions as anti- spermatogenic contraceptive agents. Success in these endeavors will provide essential data needed to enable ultimately moving H2-GMZ into pre-clinical toxicology and registration as an FDA IND for the start of clinical trials in humans.