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Discovery of 4-(1,2,4-Oxadiazol-5-yl)azepan-2-one Derivatives as a New Class of Cannabinoid Type 2 Receptor Agonists for the Treatment of Inflammatory Pain
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-23 , DOI: 10.1021/acs.jmedchem.2c01943 Jinshan Nan 1 , Jingming Liu 1 , Guifeng Lin 1 , Shanshan Zhang 1 , Anjie Xia 1 , Pei Zhou 2 , Yangli Zhou 1 , Jiahao Zhang 1 , Jinlong Zhao 1 , Shiyu Zhang 2 , Chong Huang 1 , Yifei Wang 1 , Qian Hu 1 , Junxian Chen 3 , Mingli Xiang 1 , Xin Yang 1 , Shengyong Yang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-23 , DOI: 10.1021/acs.jmedchem.2c01943 Jinshan Nan 1 , Jingming Liu 1 , Guifeng Lin 1 , Shanshan Zhang 1 , Anjie Xia 1 , Pei Zhou 2 , Yangli Zhou 1 , Jiahao Zhang 1 , Jinlong Zhao 1 , Shiyu Zhang 2 , Chong Huang 1 , Yifei Wang 1 , Qian Hu 1 , Junxian Chen 3 , Mingli Xiang 1 , Xin Yang 1 , Shengyong Yang 1
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Selectively targeting the cannabinoid receptor CB2 is an attractive therapeutic strategy for the treatment of inflammatory pain without psychiatric side effects mediated by the cannabinoid receptor CB1. Herein, we report the discovery of 4-(1,2,4-oxadiazol-5-yl)azepan-2-one derivatives as a new class of CB2 agonists. Systematic structure–activity relationship investigations resulted in the identification of the most potent compound 25r. This compound displayed high selectivity for CB2 against CB1 (CB2 EC50 = 21.0 nM, Emax = 87%, CB1 EC50 > 30 μM, ratio CB1/CB2 > 1428) with favorable pharmacokinetic properties. Especially, 25r demonstrated significant efficacy in the analgesic model of rodent inflammatory pain. All the results suggest that compound 25r could serve as a lead compound for treating inflammatory pain and deserves further in-depth studies.
中文翻译：
发现 4-(1,2,4-Oxadiazol-5-yl)azepan-2-one 衍生物作为一类新的大麻素 2 型受体激动剂用于治疗炎症性疼痛
选择性地靶向大麻素受体 CB2 是一种有吸引力的治疗策略，用于治疗炎症性疼痛，而没有大麻素受体 CB1 介导的精神副作用。在此，我们报告发现 4-(1,2,4-oxadiazol-5-yl)azepan-2-one 衍生物作为一类新的 CB2 激动剂。系统的构效关系研究导致鉴定出最有效的化合物25r。该化合物显示出 CB2 对 CB1 的高选择性（CB2 EC 50 = 21.0 nM，E max = 87%，CB1 EC 50 > 30 μM，比率 CB1/CB2 > 1428），具有良好的药代动力学特性。特别是，25r在啮齿动物炎症性疼痛的镇痛模型中显示出显着的疗效。所有结果表明，化合物25r可以作为治疗炎症性疼痛的先导化合物，值得进一步深入研究。
更新日期：2023-02-23
中文翻译：
发现 4-(1,2,4-Oxadiazol-5-yl)azepan-2-one 衍生物作为一类新的大麻素 2 型受体激动剂用于治疗炎症性疼痛
选择性地靶向大麻素受体 CB2 是一种有吸引力的治疗策略，用于治疗炎症性疼痛，而没有大麻素受体 CB1 介导的精神副作用。在此，我们报告发现 4-(1,2,4-oxadiazol-5-yl)azepan-2-one 衍生物作为一类新的 CB2 激动剂。系统的构效关系研究导致鉴定出最有效的化合物25r。该化合物显示出 CB2 对 CB1 的高选择性（CB2 EC 50 = 21.0 nM，E max = 87%，CB1 EC 50 > 30 μM，比率 CB1/CB2 > 1428），具有良好的药代动力学特性。特别是，25r在啮齿动物炎症性疼痛的镇痛模型中显示出显着的疗效。所有结果表明，化合物25r可以作为治疗炎症性疼痛的先导化合物，值得进一步深入研究。
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