Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IkappaB kinase-beta (IKK-beta)

J Med Chem. 2009 May 14;52(9):3098-102. doi: 10.1021/jm9000117.

Abstract

The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.

MeSH terms

  • Drug Discovery*
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / metabolism
  • Inhibitory Concentration 50
  • Isoquinolines / chemistry*
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Isoquinolines
  • Protein Kinase Inhibitors
  • I-kappa B Kinase