Structural determinants for histamine H1 affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs

被引：12

作者：

Aslanian, Robert ^{[1
]}

Piwinski, John J. ^{[1
]}

Zhu, Xiaohong ^{[1
]}

Priestley, Tony ^{[1
]}

Sorota, Steve ^{[1
]}

Du, Xiao-Yi ^{[1
]}

Zhang, Xue-Song ^{[1
]}

McLeod, Robbie L. ^{[1
]}

West, Robert E. ^{[1
]}

Williams, Shirley M. ^{[1
]}

Hey, John A. ^{[1
]}

机构：

[1] Schering Plough Res Inst, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 17期

关键词：

Antihistamine; Terfenadine; Astemizole; Torsades de pointes; hERG; H-1; MUTATIONAL ANALYSIS; POTASSIUM CHANNEL; GUINEA-PIGS; DE-POINTES; DRUGS; RECEPTOR; ANTIHISTAMINES; ANTAGONIST; INSIGHTS; INTERVAL;

D O I：

10.1016/j.bmcl.2009.07.047

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H-1 binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H-1 assays. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5043 / 5047

页数：5

共 17 条

[1]

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[2]

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H1 receptor [J].