A focused screening strategy identified a thienopyrimidine as a hCB2 cannabinoid receptor agonist with modest selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure activity relationships described here outline the optimization and modification to a more polar purine core. Examples from this novel purine series were found to be highly potent and fully efficaceous agonists of the human CB2 receptor with excellent selectivity against CB1. Some of these molecules have attractive rat and dog pharmacodynamic (PK) profiles and have demonstrated robust oral activity in rodent models of joint pain.Herin we report on the discovery and structure activity relationships of this new structural class of selective CB2 agonists.

Discovery and optimization of novel purines as potent and selective CB2 agonists

244th National Meeting (2012)

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