Novel tricyclic inhibitors of IKK2: discovery and SAR leading to the identification of 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066)

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7006-12. doi: 10.1016/j.bmcl.2011.09.111. Epub 2011 Oct 5.

Abstract

The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / pharmacology
  • Administration, Oral
  • Animals
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / chemistry*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • Inflammatory Bowel Diseases / drug therapy
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimiazo(4,5-d)pyrrolo(2,3-b)pyridin-7-yl)pyridin-2-yl)methyl)acetamide
  • Acetamides
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • I-kappa B Kinase
  • Ikbkb protein, mouse