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.

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 . This compound displayed high selectivity for CB2 against CB1 (CB2 EC = 21.0 nM, = 87%, CB1 EC > 30 μM, ratio CB1/CB2 > 1428) with favorable pharmacokinetic properties. Especially, demonstrated significant efficacy in the analgesic model of rodent inflammatory pain. All the results suggest that compound could serve as a lead compound for treating inflammatory pain and deserves further in-depth studies.