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

被引：18

作者：

Zhang, Qingwei ^{[1
]}

Xia, Zhiren ^{[1
]}

Joshi, Shailen ^{[1
]}

Scott, Victoria E. ^{[1
]}

Jarvis, Michael F. ^{[1
]}

机构：

[1] AbbVie, Neurosci Res, N Chicago, IL 60064 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 06期

关键词：

Ca(v)3.2; T-type calcium channel; pain; sulfonamides; ADME; NEUROPATHIC PAIN; SENSORY NEURONS; N-TYPE; RATS; TREMOR;

D O I：

10.1021/acsmedchemlett.5b00023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of a novel peripherally acting and selective Ca(v)3.2 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.

引用

收藏

页码：641 / 644

页数：4

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