Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release

J Med Chem. 2001 Oct 11;44(21):3351-4. doi: 10.1021/jm0155502.

Abstract

SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Binding Sites
  • Heterocyclic Compounds, 1-Ring / chemical synthesis*
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacology
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology
  • Lipopolysaccharides / pharmacology
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 2,11-diaza--4-(2-(trifluoromethyl)phenyl)-5-(hydroxyaminocarbonyl)-1-((((piperazin-1-yl)carbonyl)methyl)aminocarbonyl)-9-oxa-3,10-dioxocyclopentadecane
  • 2,11-diaza-4-(2-(trifluoromethyl)phenyl)-5-(hydroxyaminocarbonyl)-1-((((morpholin-4-yl)carbonyl)methyl)aminocarbonyl)-9-oxa-3,10-dioxocyclopentadecane
  • Heterocyclic Compounds, 1-Ring
  • Hydroxamic Acids
  • Lipopolysaccharides
  • Protease Inhibitors
  • Tumor Necrosis Factor-alpha
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • ADAM17 protein, human