Matrix metalloproteinase inhibitors containing a (carboxyalkyl)amino zinc ligand: modification of the P1 and P2' residues

J Med Chem. 1994 Mar 4;37(5):674-88. doi: 10.1021/jm00031a018.

Abstract

Systematic modification of the presumed P1 side chain in a series of (carboxyalkyl)amino-based inhibitors of matrix metalloproteinases enabled identification of the 2-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)ethyl group as a preferred substituent imparting potent inhibition of the enzymes collagenase and gelatinase. It was subsequently found that the P2'-P3' residues in this series could be replaced by small non-peptide residues, while maintaining inhibitory potency. The imide group in this series of compounds can undergo autocatalytic hydrolysis under neutral conditions.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Chromogenic Compounds / metabolism
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology
  • Drug Stability
  • Extracellular Matrix / enzymology*
  • Fluorescent Dyes
  • Gelatinases / antagonists & inhibitors
  • Half-Life
  • Humans
  • Hydrogen-Ion Concentration
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Isoindoles
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Molecular Sequence Data
  • Molecular Structure
  • Structure-Activity Relationship
  • Zinc*

Substances

  • Chromogenic Compounds
  • Dipeptides
  • Fluorescent Dyes
  • Indoles
  • Isoindoles
  • Matrix Metalloproteinase Inhibitors
  • (N-(1-carboxy-3-(1,3-dihydro-1,3-dioxo-2H-benz(f)isoindol-2-yl)propyl)-leucyl)-N-methyl-phenylalaninamide
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Zinc