Bioavailable pyrrolo-benzo-1,4-diazines as Nav1.7 sodium channel blockers for the treatment of pain

被引：12

作者：

Yang, Shu-Wei ^{[1
]}

Ho, Ginny D. ^{[1
]}

Tulshian, Deen ^{[1
]}

Bercovici, Ana ^{[1
]}

Tan, Zheng ^{[1
]}

Hanisak, Jennifer ^{[1
]}

Brumfield, Stephanie ^{[1
]}

Matasi, Julius ^{[1
]}

Sun, Xianfeng ^{[2
]}

Sakwa, Samuel A. ^{[2
]}

Herr, R. Jason ^{[2
]}

Zhou, Xiaoping ^{[3
]}

Bridal, Terry ^{[4
]}

Urban, Mark ^{[5
]}

Vivian, Jeffrey ^{[5
]}

Rindgen, Diane ^{[6
]}

Sorota, Steve ^{[4
]}

机构：

[1] Merck Res Lab, Discovery Chem, Kenilworth, NJ 07033 USA

[2] Albany Mol Res Inc, Dept Med Chem, Albany, NY 12203 USA

[3] Merck Res Lab, In Vivo Pharmacol Grp, Kenilworth, NJ 07033 USA

[4] Merck Res Lab, Cardiorenal Grp, Kenilworth, NJ 07033 USA

[5] Merck Res Lab, Neurosci, Kenilworth, NJ 07033 USA

[6] Merck Res Lab, Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 21期

关键词：

Na(v)1.7; Na(v)1.5; Sodium channel; Pain; GENES; EXPRESSION; MUTATION; NEURONS;

D O I：

10.1016/j.bmcl.2014.09.038

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 mu M. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4958 / 4962

页数：5

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