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 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.
['Zhang|Qingwei|Q|', 'Xia|Zhiren|Z|', 'Joshi|Shailen|S|', 'Scott|Victoria E|VE|', 'Jarvis|Michael F|MF|']
ADME sulfonamides T-type calcium channel Cav3.2 pain