Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents

Bioorg Med Chem Lett. 2008 Mar 1;18(5):1577-82. doi: 10.1016/j.bmcl.2008.01.075. Epub 2008 Jan 26.


Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM17 Protein
  • Animals
  • Area Under Curve
  • Benzamides / blood
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Biological Availability
  • Dogs
  • Half-Life
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship


  • Benzamides
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, rat