title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Gerard M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Celestine T
authors.initials: CT
authors.lastname: O'Shaughnessy
authors.forename: Alan
authors.initials: A
authors.lastname: Naylor
authors.forename: William L
authors.initials: WL
authors.lastname: Mitchell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Eatherton
authors.forename: Brian P
authors.initials: BP
authors.lastname: Slingsby
authors.forename: D Anthony
authors.initials: DA
authors.lastname: Rawlings
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
authors.forename: Carl P
authors.initials: CP
authors.lastname: Haslam
authors.forename: Nick M
authors.initials: NM
authors.lastname: Clayton
authors.forename: Alex W
authors.initials: AW
authors.lastname: Wilson
authors.forename: Iain P
authors.initials: IP
authors.lastname: Chessell
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wittington
authors.forename: Richard
authors.initials: R
authors.lastname: Green
mesh_terms: 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
chemical_list: 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