Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: Discovery, optimization, and biological evaluation

Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamides as a novel series possessing significant CB₂ receptor affinity and selectivity. Four sets of triaryl ligands were designed and synthesized for further structural modifications and led to the identification of eight compounds as potent and selective CB₂ inverse agonists with high binding affinity (CB₂K_i < 10 nM). Especially, compound 57 exhibited the strongest binding affinity on the CB₂ receptor (CB₂K_i of 0.5 nM) and the best selectivity over the CB₁ receptor (selectivity index of 2594). Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and it was confirmed by a cell viability assay that the inhibition effects were not derived from the cytotoxicity. Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB₂ receptor binding affinity.