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

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.

Compound 6b (CBS0550) had high affinity for the human CB2 receptor (CB2 IC50 = 2.9 nM, EC50 = 1.8 nM, Emax = 85%), and orally administered compound 6b significantly reversed mechanical hyperalgesia in the Randall–Selitto model of inflammatory pain in rats.Figure optionsDownload as PowerPoint slide