The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors

Bioorg Med Chem Lett. 1998 Aug 18;8(16):2087-92. doi: 10.1016/s0960-894x(98)00396-5.

Abstract

A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.

MeSH terms

  • Collagenases / chemistry*
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Indicators and Reagents
  • Kinetics
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase Inhibitors*
  • Models, Molecular
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemistry
  • Phenylalanine / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Succinates / chemical synthesis
  • Succinates / chemistry
  • Succinates / pharmacology
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology

Substances

  • Hydroxamic Acids
  • Indicators and Reagents
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Succinates
  • Thiophenes
  • Phenylalanine
  • batimastat
  • Collagenases
  • Matrix Metalloproteinase 8