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发现2-[(2,4-二氯苯基)氨基]-N-[(四氢-2H-吡喃-4-基)甲基]-4-(三氟甲基)-5-嘧啶甲酰胺，一种用于治疗炎性疼痛的选择性CB2受体激动剂。

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.

作者信息

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

机构信息

Neurology and GI Centre of Excellence for Drug Discovery, Molecular Discovery Research, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, CM19 5AW, UK.

出版信息

J Med Chem. 2007 May 31;50(11):2597-600. doi: 10.1021/jm061195+. Epub 2007 May 4.

DOI:10.1021/jm061195+
PMID:17477516
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.

摘要

选择性CB2受体激动剂有望成为治疗炎症性疼痛和神经性疼痛的潜在治疗药物。一项重点筛选确定了一种嘧啶酯作为CB2受体的部分激动剂，其效力为微摩尔级。随后的先导化合物优化确定了35（GW842166X）为该系列中的最佳化合物。在大鼠佐剂性关节炎（FCA）炎症性疼痛模型中，35的口服半数有效剂量（ED50）为0.1mg/kg，并被选为该适应症的临床候选药物。

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