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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties
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Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties

机译：噻唑和苯并噻唑衍生物作为具有体内抗炎特性的选择性大麻素CB2激动剂的结构 - 活性关系

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摘要

The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d] thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with K(i)s in the picomolar or low nanomolar range, and selectivity indices (K-i hCB1/K-i hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC(50)s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：CB2受体激动剂用作缺乏精神病副作用消炎药的治疗强劲潜力已经引起了巨大关注。本文中，我们描述对CB1和CB2受体的合理设计和新颖的噻唑并苯并噻唑衍生物的合成以及它们的结合亲和力的评估和功能活性。具有通式的N-（3-戊基苯并[d]噻唑-2（3H） - 亚基）甲酰胺（化合物6A-6D）的系列显示出朝向CB 2受体具有K的最高亲和力和选择性（I）S IN皮摩尔或低纳摩尔范围内，并且选择性指数（KI HCB1 / HCB2的Ki）达到高达429倍。值得注意的是，这些化合物也表现出激动性官能在细胞试验与EC在低纳摩尔范围内的活性（50）秒。更有趣的是，化合物6D中，3-（三氟甲基）苯甲酰胺衍生物，表现出对DSS诱导的急性显着保护结肠炎小鼠模型。 （c）2019年Elsevier Masson SAS。版权所有。

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