Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 1: lead identification

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4293-7. doi: 10.1016/j.bmcl.2003.09.056.

Abstract

Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hydroxamic Acids / pharmacology
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Conformation
  • Protease Inhibitors / pharmacology
  • Pyrazines / pharmacology
  • Structure-Activity Relationship
  • Succinates / chemical synthesis
  • Succinates / chemistry
  • Succinates / pharmacology*
  • Sulfonamides / pharmacology

Substances

  • CGS 27023A
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Protease Inhibitors
  • Pyrazines
  • Succinates
  • Sulfonamides
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein