Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships

J Med Chem. 2002 Nov 7;45(23):4954-7. doi: 10.1021/jm0255670.

Abstract

New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Administration, Oral
  • Animals
  • Biological Availability
  • Dogs
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology
  • Matrix Metalloproteinase 3 / chemistry
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Swine

Substances

  • Hydroxamic Acids
  • IK 682
  • Lactams
  • Protease Inhibitors
  • ADAM Proteins
  • Metalloendopeptidases
  • Matrix Metalloproteinase 3
  • ADAM17 Protein
  • Adam17 protein, rat