Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T‑Type Calcium Channel Blocker, ABT-639

The discovery of a novel peripherally acting and selective Ca_v3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits <b>1</b> and <b>2</b>, which have poor metabolic stability, were optimized to obtain <b>4</b>, which has improved stability and oral bioavailability. Modification of <b>4</b> to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat