Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE)

Bioorg Med Chem Lett. 2007 Jan 1;17(1):266-71. doi: 10.1016/j.bmcl.2006.09.048. Epub 2006 Oct 5.

Abstract

Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM17 Protein
  • Barbiturates / chemical synthesis
  • Barbiturates / chemistry*
  • Barbiturates / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • Hydroxamic Acids / chemistry
  • Inhibitory Concentration 50
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*

Substances

  • Barbiturates
  • Benzamides
  • Hydroxamic Acids
  • N-(4-(methanesulfonylpiperazin-1-yl)-2,4,6-trioxopyrimidin-4-ylmethyl)-4-((2-methylquinolin-4-yl)methoxy)benzamide
  • Protease Inhibitors
  • ADAM Proteins
  • ADAM17 Protein