Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain

被引：35

作者：

Wu, Yong-Jin ^{[1
]}

Guernon, Jason ^{[1
]}

Shi, Jianliang ^{[1
]}

Ditta, Jonathan ^{[1
]}

Robbins, Kevin J. ^{[1
]}

Rajamani, Ramkumar ^{[1
]}

Easton, Amy ^{[1
]}

Newton, Amy ^{[1
]}

Bourin, Clotilde ^{[1
]}

Mosure, Kathleen ^{[1
]}

Soars, Matthew G. ^{[1
]}

Knox, Ronald J. ^{[1
]}

Matchett, Michele ^{[1
]}

Pieschl, Rick L. ^{[1
]}

Post-Munson, Debra J. ^{[1
]}

Wang, Shuya ^{[1
]}

Herrington, James ^{[1
]}

Graef, John ^{[1
]}

Newberry, Kimberly ^{[1
]}

Bristow, Linda J. ^{[1
]}

Meanwell, Nicholas A. ^{[1
]}

Olson, Richard ^{[1
]}

Thompson, Lorin A. ^{[1
]}

Dzierba, Carolyn ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, 5 Res Pkwy, Wallingford, CT 06492 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 06期

关键词：

SODIUM-CHANNEL NA(V)1.7; OF-FUNCTION MUTATIONS; DISCOVERY; SCN9A; ANTAGONISTS;

D O I：

10.1021/acs.jmedchem.6b01918

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine-and piperidine-based benzenesulfonamides as potent and selective Na(v)1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.

引用

页码：2513 / 2525

页数：13

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