Discovery of N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamides as potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE)

Bioorg Med Chem Lett. 2003 Jun 16;13(12):2035-40. doi: 10.1016/s0960-894x(03)00313-5.

Abstract

New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFalpha production in a human whole blood assay (WBA) with an IC(50) of 0.42 micro M.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / pharmacology*
  • Animals
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Lactams / chemistry
  • Lactams / pharmacology
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Structure-Activity Relationship
  • Swine
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Acetamides
  • Enzyme Inhibitors
  • Lactams
  • Matrix Metalloproteinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • ADAM17 protein, human