Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic action Original Research Article

In this study, a novel series of CB2 receptor agonist imine derivatives, 1–6, was synthesized and evaluated for activity against the CB2 receptor. In a previous paper we reported the synthesis and SARs of thiazole derivative 1, a potent CB2 receptor agonist, but we had not assessed chemical modifications of the 5-membered heteroring of 1. In the present study, we therefore tried chemically modifying the 5-membered heteroring of 1 in an attempt to further improve binding affinity for the CB2 receptor. In the course of making the structural modifications, we discovered that a novel pyrazole derivative 6b (CBS0550) had high affinity for the CB2 receptor (IC50 = 2.9 nM, EC50 = 1.8 nM, Emax = 85%), high selectivity for CB2 (CB1 IC50/CB2 IC50 = 1400), and good physicochemical properties (solubility in water: 5.9 mg/100 mL at 25 °C). Oral administration of 6b to rats at a dose of 10 mg/kg resulted in significant plasma concentrations, and orally administered compound 6b significantly reversed mechanical hyperalgesia in the Randall–Selitto model of inflammatory pain in rats.