Design and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases

J Med Chem. 1999 Jan 14;42(1):87-94. doi: 10.1021/jm980142s.

Abstract

A new series of hydroxamic acid-based matrix metalloproteinase (MMP) inhibitors containing a unique phosphinamide motif derived from D-amino acid was designed, synthesized, and tested for enzyme inhibition. Compounds with an R configuration at phosphorus were found to be potent MMP inhibitors while molecules with the S configuration were almost inactive. Structure-activity relationship studies of the series led to the discovery of the potent inhibitor 16 with IC50 = 20.5 nM and 24.4 nM against fibroblast collagenase (MMP-1) and stromelysin (MMP-3), respectively. The binding mode of this novel phosphinamide-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 16.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / metabolism
  • Hydroxamic Acids / pharmacology
  • Matrix Metalloproteinase 1
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 3 / metabolism
  • Matrix Metalloproteinase 7
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / metabolism
  • Organophosphorus Compounds / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology
  • Recombinant Proteins / antagonists & inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • N-hydroxy-2-((methylphenylphosphinyl)benzylamino)-4-methylpentanamide
  • Organophosphorus Compounds
  • Protease Inhibitors
  • Recombinant Proteins
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 7
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 1