Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current IKs

被引：15

作者：

Ahmad, S ^{[1
]}

Doweyko, L ^{[1
]}

Ashfaq, A ^{[1
]}

Ferrara, FN ^{[1
]}

Bisaha, SN ^{[1
]}

Schmidt, JB ^{[1
]}

DiMarco, J ^{[1
]}

Conder, ML ^{[1
]}

Jenkins-West, T ^{[1
]}

Normandin, DE ^{[1
]}

Russell, AD ^{[1
]}

Smith, MA ^{[1
]}

Levesque, PC ^{[1
]}

Lodge, NJ ^{[1
]}

Lloyd, J ^{[1
]}

Stein, PD ^{[1
]}

Atwal, KS ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 01期

关键词：

D O I：

10.1016/j.bmcl.2003.10.003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I-Kr). The block of I-Kr can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I-Kr, the role of the slow component of the delayed rectifier potassium current (I-Ks) becomes significant only at faster heart rate. Therefore selective blockers Of I-Ks could prolong APD with a reduced propensity to cause proarrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I-Ks inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC50 > 30 nM) and up to 40-fold I-Ks/I-Kr selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：99 / 102

页数：4

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