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 25r. This compound displayed high
selectivity for CB2 against CB1 (CB2 EC50 = 21.0 nM, Emax = 87%, CB1 EC50 > 30 μM,
ratio CB1/CB2 > 1428) with favorable pharmacokinetic properties.
Especially, 25r demonstrated significant efficacy in
the analgesic model
of rodent inflammatory pain. All the results suggest that compound 25r could serve as a lead compound for treating inflammatory
pain and deserves further in-depth studies.