Design and synthesis of phenylisoxazole derivatives as novel human acrosin inhibitors

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2802-6. doi: 10.1016/j.bmcl.2014.04.118. Epub 2014 May 9.

Abstract

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.

Keywords: Guanidinophenylpyrazole derivatives; Human acrosin inhibitors; Male contraceptive; Molecular hybridization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrosin / antagonists & inhibitors*
  • Acrosin / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology*
  • Male
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Acrosin