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: Qingwei Zhang, Zhiren Xia, Shailen Joshi, Victoria E Scott, Michael F Jarvis
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 6 Issue 6 Pg. 641-4 (Jun 11 2015) ISSN: 1948-5875 [Print] United States
• PMID: 26101566 (Publication Type: Journal Article)