High concentration electrophysiology-based fragment screen: Discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors

被引：16

作者：

Wolkenberg, Scott E. ^{[1
]}

Zhao, Zhijian ^{[1
]}

Mulhearn, James J. ^{[1
]}

Harrison, Scott T. ^{[1
]}

Sanders, John M. ^{[2
]}

Cato, Matthew J. ^{[3
]}

Jovanovska, Aneta ^{[3
]}

Panigel, Jacqueline ^{[3
]}

Cook, Sean P. ^{[3
]}

Henze, Darrell A. ^{[3
]}

Kane, Stefanie A. ^{[3
]}

Hartman, George D. ^{[1
]}

Barrow, James C. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Mol Syst Grp, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Pain Res, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 09期

关键词：

Acid-sensing ion channel 3; Fragment screening; Electrophysiology; DRUG DESIGN;

D O I：

10.1016/j.bmcl.2010.12.115

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 mu M with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2646 / 2649

页数：4

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