Trisubstituted Sulfonamides: a New Chemotype for Development of Potent and Selective CB₂ Receptor Inverse Agonists

An extensive exploration of the SAR of a trisubstituted sulfonamides series led to the identification of 39, which is a potent and selective CB₂ receptor inverse agonist (CB₂Ki = 5.4 nM, and CB₁Ki = 500 nM). The functional properties measured by cAMP assays indicated that the selected compounds were CB₂ inverse agonists with high potency values (34, EC₅₀ = 8.2 nM, and 39, EC₅₀ = 2.5 nM). Furthermore, an osteoclastogenesis bioassay indicated that trisubstituted sulfonamide compounds showed great inhibition of osteoclast formation.