The cannabinoid receptor 2 (CB2R) 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 CB2R 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 CB2R agonists. Several examples showed high levels of activity (EC50<200 nM) and binding affinity (Ki<200 nM) for the CB2R, and no detectable activity at the CB1R. 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.
Bioorg Med Chem
241 - 263
Agonist, Cannabinoid receptor 1, Cannabinoid receptor 2, Inflammation, Ligand-based screening, Anti-Inflammatory Agents, Cannabinoid Receptor Agonists, Drug Evaluation, Preclinical, Kinetics, Ligands, Models, Molecular, Receptor, Cannabinoid, CB2, Small Molecule Libraries