Sit S Y, Conway Charlie, Bertekap Robert, Xie Kai, Bourin Clotilde, Burris Kevin, Deng Hongfeng
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
Bioorg Med Chem Lett. 2007 Jun 15;17(12):3287-91. doi: 10.1016/j.bmcl.2007.04.009. Epub 2007 Apr 10.
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.
一类双芳基咪唑衍生物被鉴定为脂肪酸酰胺水解酶（FAAH）的强效抑制剂。化合物17（IC(50)=2 nM）在大鼠热逃避试验（哈格里夫斯试验）中，以剂量依赖性方式（0.1 - 10mg/kg，静脉注射）增强外源性花生四烯酸乙醇胺（1mg/kg，静脉注射）的作用，并在持续性（福尔马林试验）和神经性（ Chung模型）疼痛的动物模型中表现出强大的抗伤害感受活性。化合物17（20mg/kg，静脉注射）在福尔马林试验中的活性与吗啡（3mg/kg，静脉注射）相当，并且被CB1拮抗剂SR141716A剂量依赖性抑制。在Chung模型中，化合物17显示出与高剂量（100mg/kg）加巴喷丁相似的抗神经病理性疼痛作用。FAAH抑制在持续性和神经性疼痛的临床治疗中显示出潜在的应用价值。
