The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist.

The development of selective CB receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CBR EC = 19 nM, CBR EC > 10 μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.