Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists

The cannabinoid receptor 2 (CB(2)R) has been linked with the regulation of inflammation, and selective receptor activation has been proposed as a target for the treatment of a range of inflammatory diseases such as atherosclerosis and arthritis. In order to identify selective CB(2)R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, we first performed a ligand-based virtual screen. Subsequent medicinal chemistry optimisation studies led to the identification of a new class of selective CB(2)R agonists. Several examples showed high levels of activity (EC(50) < 200 nM) and binding affinity (K(i) < 200 nM) for the CB(2)R, and no detectable activity at the CB(1)R. The most promising example, DIAS2, also showed favourable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.