Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket

Bioorg Med Chem. 2007 Sep 15;15(18):6170-81. doi: 10.1016/j.bmc.2007.06.031. Epub 2007 Jun 20.

Abstract

A series of beta-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1' group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-alpha production.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Hydroxamic Acids / chemistry*
  • Hydroxamic Acids / pharmacology*
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Matrix Metalloproteinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • ADAM Proteins
  • Matrix Metalloproteinases
  • ADAM17 Protein
  • Adam17 protein, mouse