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, a...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 50; no. 11; pp. 2597 - 2600
Main Authors:	Giblin, Gerard M. P, O'Shaughnessy, Celestine T, Naylor, Alan, Mitchell, William L, Eatherton, Andrew J, Slingsby, Brian P, Rawlings, D. Anthony, Goldsmith, Paul, Brown, Andrew J, Haslam, Carl P, Clayton, Nick M, Wilson, Alex W, Chessell, Iain P, Wittington, Andrew R, Green, Richard
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 31-05-2007
Subjects:	Analgesics Analgesics - chemical synthesis Analgesics - pharmacokinetics Analgesics - pharmacology Animals Biological and medical sciences Biological Availability Half-Life Humans Inflammation - drug therapy Inflammation - metabolism Medical sciences Miscellaneous Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pain - drug therapy Pain - metabolism Pharmacology. Drug treatments Pyrans - chemical synthesis Pyrans - pharmacokinetics Pyrans - pharmacology Pyrimidines - chemical synthesis Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Rats Receptor, Cannabinoid, CB2 - agonists Structure-Activity Relationship Agonist Rat Nitrogen heterocycle Selectivity Hyperalgesia Pain Structure activity relation Six membered ring Chemical synthesis Human Rodentia Benzene derivatives Pyran derivatives Oral administration CB2 cannabinoid receptor Bioavailability In vitro In vivo Vertebrata Chemotherapy Mammalia Treatment Analgesic Animal Affinity Fluorine Organic compounds Pharmacokinetics
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Summary:	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.
Bibliography:	ark:/67375/TPS-CLJ9WT45-T istex:FE0C1C9EF2CE1EF934D03154B72D453B72E5688E ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm061195+