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.