title: Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.
abstract: 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.
authors.affiliation: Neuroscience Research, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Neuroscience Research, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Neuroscience Research, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Neuroscience Research, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Scott
authors.affiliation: Neuroscience Research, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
keywords: ADME; Cav3.2; T-type calcium channel; pain; sulfonamides