Design and synthesis of phenylisoxazole derivatives as novel human acrosin inhibitors.

Human acrosin is an attractive target for the discovery of novel male contraceptives. Isoxazole derivative ISO-1, a small-molecule weak human acrosin inhibitor, was used as the starting point for lead optimization. After two rounds of structure-based inhibitor design, a highly potent inhibitor B6 (IC50=1.44 µM) was successfully identified, which showed good selectivity over trypsin and represents one of the most active human acrosin inhibitors up to date.