Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro- 2H-pyran-4-yl)methyl]-4-(trifluoromethyl)- 5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain.
Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.
Giblin
Gerard M P
GM
Neurology and GI Centre of Excellence for Drug Discovery, Molecular Discovery Research, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, CM19 5AW, UK. ged.m.giblin@gsk.com
O'Shaughnessy
Celestine T
CT
Naylor
Alan
A
Mitchell
William L
WL
Eatherton
Andrew J
AJ
Slingsby
Brian P
BP
Rawlings
D Anthony
DA
Goldsmith
Paul
P
Brown
Andrew J
AJ
Haslam
Carl P
CP
Clayton
Nick M
NM
Wilson
Alex W
AW
Chessell
Iain P
IP
Wittington
Andrew R
AR
Green
Richard
R
D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D006207:Half-Life; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
C520846:2-((2,4-dichlorphenyl)amino)-N-((tetrahydro-2H-pyran-4-yl)methyl)-4-(trifluoromethyl)-5-pyrimidinecarboxamide; D000700:Analgesics; D011714:Pyrans; D011743:Pyrimidines; D043885:Receptor, Cannabinoid, CB2