Discovery of 1-[4-(3-chlorophenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]-1-morpholin-4-ylmethanone (GSK554418A), a brain penetrant 5-azaindole CB2 agonist for the treatment of chronic pain

J Med Chem. 2009 Oct 8;52(19):5785-8. doi: 10.1021/jm9009857.

Abstract

We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.

MeSH terms

  • Aminopyridines / pharmacokinetics
  • Aminopyridines / therapeutic use*
  • Animals
  • Aza Compounds
  • Brain / metabolism*
  • CHO Cells
  • Cell Line
  • Chronic Disease
  • Cricetinae
  • Cricetulus
  • Drug Discovery
  • Humans
  • Indoles
  • Morpholines / pharmacokinetics
  • Morpholines / therapeutic use*
  • Pain / drug therapy*
  • Rats
  • Receptor, Cannabinoid, CB2 / agonists*
  • Structure-Activity Relationship

Substances

  • 1-(4-(3-chlorophenylamino)-1-methyl-1H-pyrrolo(3,2-c)pyridin-7-yl)-1-morpholin-4-ylmethanone
  • 5-azaindole
  • Aminopyridines
  • Aza Compounds
  • Indoles
  • Morpholines
  • Receptor, Cannabinoid, CB2