Heterocycle-based MMP inhibitors with P2' substituents

Bioorg Med Chem Lett. 2001 Apr 23;11(8):1009-13. doi: 10.1016/s0960-894x(01)00137-8.

Abstract

Potent and selective inhibition of matrix metalloproteinases was demonstrated for a series of sulfonamide-based hydroxamic acids. The design of the heterocyclic sulfonamides incorporates a six- or seven-member central ring with a P2' substituent that can be modified. Binding interactions of this substituent at the S2' site are believed to contribute to high inhibitory potency against stromelysin, collagenase-3 and gelatinases A and B, and to provide selectivity against collagenase-1 and matrilysin. An X-ray structure of a stromelysin inhibitor complex was obtained to provide insights into the SAR and selectivity trends observed for the series.

MeSH terms

  • Collagenases
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds, 1-Ring / chemical synthesis
  • Heterocyclic Compounds, 1-Ring / pharmacology*
  • Inhibitory Concentration 50
  • Macromolecular Substances
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase Inhibitors*
  • Sensitivity and Specificity
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds, 1-Ring
  • Macromolecular Substances
  • Matrix Metalloproteinase Inhibitors
  • Sulfonamides
  • Collagenases
  • Matrix Metalloproteinase 13
  • collagenase 1