Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 2: lead optimization

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4299-304. doi: 10.1016/j.bmcl.2003.09.057.

Abstract

Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.

MeSH terms

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

Substances

  • Enzyme Inhibitors
  • Succinates
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein