Discovery and SAR of hydantoin TACE inhibitors

Bioorg Med Chem Lett. 2010 Mar 15;20(6):1877-80. doi: 10.1016/j.bmcl.2010.01.148. Epub 2010 Feb 4.

Abstract

We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM17 Protein
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hydantoins / chemistry
  • Hydantoins / pharmacology*
  • Hydrogen Bonding
  • Models, Molecular
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Enzyme Inhibitors
  • Hydantoins
  • ADAM Proteins
  • ADAM17 Protein