N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis

J Med Chem. 2009 Aug 13;52(15):4757-73. doi: 10.1021/jm900261f.

Abstract

Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage degradation and to halt the progression of OA. Herein, we report the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors possessing an arylsulfonamidic scaffold. Among these potential inhibitors, a very promising compound was discovered exhibiting nanomolar activity for MMP-13 and was highly selective for this enzyme compared to MMP-1, -14, and TACE. This compound acted as a slow-binding inhibitor of MMP-13 and was demonstrated to be effective in an in vitro collagen assay and in a model of cartilage degradation. Furthermore, a docking study was conducted for this compound in order to investigate its binding interactions with MMP-13 and the reasons for its selectivity toward MMP-13 versus other MMPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / chemistry
  • ADAM17 Protein
  • Cartilage / metabolism
  • Drug Design*
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use
  • Matrix Metalloproteinase 1 / chemistry
  • Matrix Metalloproteinase 13 / chemistry
  • Matrix Metalloproteinase 14 / chemistry
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Osteoarthritis / drug therapy*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Structure-Activity Relationship

Substances

  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • ADAM Proteins
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 1
  • Matrix Metalloproteinase 14
  • ADAM17 Protein