Discovery of novel guanidinophenylpyrazole human acrosin inhibitors by molecular hybridization

Human acrosin is a promising target for male contraceptives. A series of novel guanidinophenylpyrazole derivatives were rationally designed by molecular hybridization of the phenylpyrazole and guanidinobenzoate inhibitors. Most of the target compounds showed potent human acrosin inhibitory activities. In particular, compound F3 was a highly active human acrosin inhibitor (IC50 = 1.26 mu M) with good selectivity over trypsin. Molecular docking studies revealed that compound F3 formed hydrophobic and hydrogen bonding interactions with the active site of human acrosin. Compound F3 represents a promising lead compound for the development of novel male contraceptives.