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.

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.

• Authors: Gerard M P Giblin, Andrew Billinton, Michael Briggs, Andrew J Brown, Iain P Chessell, Nick M Clayton, Andrew J Eatherton, Paul Goldsmith, Carl Haslam, Matthew R Johnson, William L Mitchell, Alan Naylor, Alcide Perboni, Brian P Slingsby, Alex W Wilson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 19 Pg. 5785-8 (Oct 08 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19743867 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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