Discovering a Reversible Male Contraceptive Agent Derived from Lonidamine

[Image: see text] There is a huge demand for safe and effective non-hormonal male contraceptives to prevent unintended pregnancy, but research on male contraceptive drugs lacks far behind the pills for women. Lonidamine and its analog adjudin are two of the best studied potential male contraceptives. However, the acute toxicity of lonidamine and the subchronic toxicity of adjudin had impeded their development for male contraception. Here, we designed and synthesized a whole new series of molecules derived from lonidamine according to a structure ligand-based design strategy and obtained a new effective and reversible contraceptive agent (BHD), and their efficacy was demonstrated in male mice and rats. Results showed that BHD had a 100% contraceptive effect on male mice after 2 weeks following a single oral dose of BHD at 100 mg/kg body weight (b.w.) or 500 mg/kg b.w. treatments. The fertility of mice was reduced to 90 and 50% after 6 weeks with a single oral dose of BHD-100 and BHD-500 mg/kg b.w. treatments, respectively. We also revealed that BHD induced the apoptosis of spermatogenic cells rapidly and disrupted the blood–testis barrier effectively. It appears to be a new potential male contraceptive candidate for future development.