Synthesis, SAR, and biological evaluation of alpha-sulfonylphosphonic acids as selective matrix metalloproteinase inhibitors

ChemMedChem. 2009 Mar;4(3):352-62. doi: 10.1002/cmdc.200800324.

Abstract

Eleven simple alpha-sulfonylphosphonates, new analogues of previously reported alpha-sulfonylaminophosphonates, were prepared and tested as MMP inhibitors. The IC(50) values of most of these compounds are in the nanomolar range against MMP-2, -8, -13, and -14. Compound 11 proved to be the most effective inhibitor of MMP-2 (IC(50) = 60 nM), with interesting selectivity versus the antitarget enzymes MMP-3 and MMP-9. The mode of binding of the new phosphonates in the active site of MMP-2 was studied, and variations in inhibition was explained by means of molecular modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Humans
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / metabolism*
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Protein Binding
  • Structure-Activity Relationship
  • Sulfonic Acids / chemical synthesis*
  • Sulfonic Acids / chemistry
  • Sulfonic Acids / pharmacology

Substances

  • Matrix Metalloproteinase Inhibitors
  • Organophosphonates
  • Sulfonic Acids
  • Matrix Metalloproteinases