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.
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.
Giblin
Gerard M P
GM
Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. ged.m.giblin@gsk.com
Billinton
Andrew
A
Briggs
Michael
M
Brown
Andrew J
AJ
Chessell
Iain P
IP
Clayton
Nick M
NM
Eatherton
Andrew J
AJ
Goldsmith
Paul
P
Haslam
Carl
C
Johnson
Matthew R
MR
Mitchell
William L
WL
Naylor
Alan
A
Perboni
Alcide
A
Slingsby
Brian P
BP
Wilson
Alex W
AW
D000631:Aminopyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001372:Aza Compounds; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D002908:Chronic Disease; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D006801:Humans; D007211:Indoles; D009025:Morpholines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
C544813:1-(4-(3-chlorophenylamino)-1-methyl-1H-pyrrolo(3,2-c)pyridin-7-yl)-1-morpholin-4-ylmethanone; C512290:5-azaindole; D000631:Aminopyridines; D001372:Aza Compounds; D007211:Indoles; D009025:Morpholines; D043885:Receptor, Cannabinoid, CB2