Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors

被引：6

作者：

Schenkel, Laurie B. ^{[1
]}

DiMauro, Erin F. ^{[1
]}

Nguyen, Hanh N. ^{[1
]}

Chakka, Nagasree ^{[1
]}

Du, Bingfan ^{[1
]}

Foti, Robert S. ^{[2
]}

Guzman-Perez, Angel ^{[1
]}

Jarosh, Michael ^{[3
]}

La, Daniel S. ^{[1
]}

Ligutti, Joseph ^{[4
]}

Milgram, Benjamin C. ^{[1
]}

Moyer, Bryan D. ^{[4
]}

Peterson, Emily A. ^{[1
]}

Roberts, John ^{[2
]}

Yu, Violeta L. ^{[3
]}

Weiss, Matthew M. ^{[1
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery, 360 Binney St, Cambridge, MA 02142 USA

[2] Amgen Inc, Dept Pharmacokinet & Drug Metab, 360 Binney St, Cambridge, MA 02142 USA

[3] Amgen Inc, Dept Neurosci, 360 Binney St, Cambridge, MA 02142 USA

[4] Amgen Inc, Dept Neurosci, One Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2017年 / 27卷 / 16期

关键词：

Sodium channel; Na(V)1.7; Na(V)1.5; State-dependent; Pain; SODIUM-CHANNELS; PAIN; SULFONAMIDES; MUTATIONS; SCN9A; PHARMACOKINETICS; EFFICACY;

D O I：

10.1016/j.bmcl.2017.06.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The Na(v)1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over Na(v)1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of Na(v)1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat Na(v)1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：3817 / 3824

页数：8

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