Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides

J Med Chem. 1997 Mar 14;40(6):1026-40. doi: 10.1021/jm960465t.

Abstract

Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).

MeSH terms

  • Animals
  • Arthritis / drug therapy
  • Binding Sites
  • Cartilage / drug effects
  • Crystallography, X-Ray
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / metabolism
  • Dipeptides / pharmacology*
  • Disease Models, Animal
  • Gelatinases / antagonists & inhibitors
  • Interleukin-1 / administration & dosage
  • Interleukin-1 / pharmacology
  • Magnetic Resonance Spectroscopy
  • Matrix Metalloproteinase 1
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase Inhibitors*
  • Metalloendopeptidases / antagonists & inhibitors
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology*
  • Rabbits
  • Rats
  • Recombinant Proteins / antagonists & inhibitors
  • Structure-Activity Relationship
  • Transferrin / metabolism
  • Zinc / chemistry
  • Zinc / metabolism

Substances

  • Dipeptides
  • Interleukin-1
  • L 758354
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Recombinant Proteins
  • Transferrin
  • N-(1-carboxyethyl)-alpha-(2-phenylethyl)glycyl-leucine, N-phenylamide
  • Gelatinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 1
  • Zinc