Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors

Bioorg Med Chem Lett. 2006 May 15;16(10):2699-704. doi: 10.1016/j.bmcl.2006.02.015. Epub 2006 Mar 3.

Abstract

A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM17 Protein
  • Animals
  • Cell Line
  • Cyclization
  • Humans
  • Mice
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Protease Inhibitors
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse