Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8)

J Med Chem. 1998 Jan 29;41(3):339-45. doi: 10.1021/jm9706426.

Abstract

For most of the known synthetic inhibitors of matrix metalloproteinases (MMPs), a substrate-like binding mode was postulated on the basis of X-ray crystallographic structures of MMP/inhibitor complexes. Conversely, the malonic acid-based inhibitor (2R,S)-HONH-CO-CH(i-Bu)-CO-Ala-Gly-NH2 was found to bind in a surprisingly different manner. Using this compound as a new lead structure, the interaction sites with human neutrophil collagenase (MMP8) were optimized with a series of iteratively designed analogues and with the help of X-ray structural analysis of selected inhibitors to finally produce low molecular weight nonpeptidic compounds of 500-1000-fold improved inhibitory potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Malonates / chemistry*
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase Inhibitors*
  • Molecular Structure
  • Spectrometry, Mass, Fast Atom Bombardment

Substances

  • Enzyme Inhibitors
  • Malonates
  • Matrix Metalloproteinase Inhibitors
  • malonic acid
  • Matrix Metalloproteinase 8