4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5222-6. doi: 10.1016/j.bmcl.2012.06.065. Epub 2012 Jun 26.

Abstract

The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.

MeSH terms

  • Animals
  • Biological Availability
  • Disease Models, Animal
  • Half-Life
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Lung / metabolism
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Rats
  • Structure-Activity Relationship

Substances

  • 7-azaindole dimer
  • Indoles
  • Protein Kinase Inhibitors
  • I-kappa B Kinase