College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
CAS Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Eur J Med Chem. 2017 Sep 8;137:598-611. doi: 10.1016/j.ejmech.2017.05.060. Epub 2017 May 30.
Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC = 3.665 ± 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series.
在此，我们通过构象跳跃和生物等排策略的结合，设计并合成了一系列哒嗪-3-甲酰胺类化合物，以期获得 CB2 选择性激动剂。通过钙动员实验评估了这些化合物的潜在活性。在测试的衍生物中，超过一半的化合物表现出中等至强的 CB2 激动剂活性。有 6 个化合物的 EC 值低于 35nM，并且一些衍生物在 CB2 受体上也表现出显著增强的效力和高选择性，超过 CB1 受体。具体而言，化合物 26 表现出最高的 CB2 激动剂活性（EC=3.665±0.553nM）和对 CB1 的显著选择性（选择性指数>2729）。此外，还测量了一些代表性化合物的 logPs，以显示与 GW842166X 相比，其值显著降低。此外，还进行了对接模拟以解释该系列的相互作用模式。
