Lilly Research Laboratories, A Division of Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
J Med Chem. 2013 Jul 25;56(14):5722-33. doi: 10.1021/jm400305d. Epub 2013 Jul 3.
A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 μM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.
聚焦筛选策略鉴定噻吩并嘧啶 12 为一种大麻素受体 2 型激动剂（hCB2），对 hCB1 受体具有中等选择性。这个初始命中化合物在体外代谢稳定性差，体内清除率高。构效关系描述了对新的更极性嘌呤 CB2 激动剂系列的优化和修饰。从这个新骨架中发现的例子是高度有效的人类 CB2 受体激动剂，对 CB1 具有优异的选择性，在测量的最高浓度（>100 μM）下通常没有 CB1 激动剂活性。化合物 26 是一种具有良好的生物制药特性的中枢穿透分子，具有高水溶性，并在啮齿动物关节疼痛模型中表现出强大的口服活性。此外，外围受限分子 22 也在相同的啮齿动物炎症性疼痛的镇痛模型中表现出显著的疗效。
