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 EC₅₀ 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 (EC₅₀ = 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.

在这里，我们描述了通过支架跳跃和生物等排策略的组合，将一系列哒嗪-3-羧酰胺设计和合成为CB2选择性激动剂。通过钙动员测定法对化合物的潜在活性进行评估。在测试的衍生物中，这些化合物中超过一半的化合物表现出中等至有效的CB2激动剂活性。六种化合物的EC ₅₀值低于35 nM，几种衍生物在CB2受体上的效力和选择性也大大高于CB1受体。具体而言，化合物26显示出最高的CB2激动剂活性（EC ₅₀ ＝ 3.665±0.553nM）和对CB1的显着选择性（选择性指数＞ 2729）。此外，与GW842166X相比，一些代表性化合物的logPs被测量为显示出明显降低的值。此外，进行了对接仿真以解释该系列的交互模式。