Optimization of ADME Properties for Sulfonamides Leadingto the Discovery of a T-Type Calcium Channel Blocker ABT-639

摘要

The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits >1 and >2, which have poor metabolic stability, were optimized to obtain >4, which has improved stability and oral bioavailability. Modification of >4 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.