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: Gerard M P Giblin, Celestine T O'Shaughnessy, Alan Naylor, William L Mitchell, Andrew J Eatherton, Brian P Slingsby, D Anthony Rawlings, Paul Goldsmith, Andrew J Brown, Carl P Haslam, Nick M Clayton, Alex W Wilson, Iain P Chessell, Andrew R Wittington, Richard Green
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 11 Pg. 2597-600 (May 31 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17477516 (Publication Type: Journal Article)

Chemical References

• 2-((2,4-dichlorphenyl)amino)-N-((tetrahydro-2H-pyran-4-yl)methyl)-4-(trifluoromethyl)-5-pyrimidinecarboxamide
• Analgesics
• Pyrans
• Pyrimidines
• Receptor, Cannabinoid, CB2

Topics

• Analgesics (chemical synthesis, pharmacokinetics, pharmacology)
• Animals
• Biological Availability
• Half-Life
• Humans
• Inflammation (drug therapy, metabolism)
• Pain (drug therapy, metabolism)
• Pyrans (chemical synthesis, pharmacokinetics, pharmacology)
• Pyrimidines (chemical synthesis, pharmacokinetics, pharmacology)
• Rats
• Receptor, Cannabinoid, CB2 (agonists)
• Structure-Activity Relationship