Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

被引：9

作者：

Skerlj, Renato ^{[1
]}

Bridger, Gary ^{[2
]}

Zhou, Yuanxi ^{[2
]}

Bourque, Elyse ^{[1
]}

McEachern, Ernest ^{[2
]}

Danthi, Sanjay ^{[1
]}

Langille, Jonathan ^{[2
]}

Harwig, Curtis ^{[2
]}

Veale, Duane ^{[2
]}

Carpenter, Bryon ^{[2
]}

Ba, Tuya ^{[2
]}

Bey, Michael ^{[2
]}

Baird, Ian ^{[2
]}

Wilson, Trevor ^{[2
]}

Metz, Markus ^{[1
]}

MacFarland, Ron ^{[2
]}

Mosi, Renee ^{[2
]}

Bodart, Veronique ^{[2
]}

Wong, Rebecca ^{[2
]}

Fricker, Simon ^{[1
]}

Huskens, Dana ^{[3
]}

Schols, Dominique ^{[3
]}

机构：

[1] Genzyme Corp, Waltham, MA 02451 USA

[2] Anormed Inc, Langley, BC V2Y 1N5, Canada

[3] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 03期

基金：

英国医学研究理事会;

关键词：

HIV-1; hERG; CCR5; chemokine receptor; LONG-QT SYNDROME; MARAVIROC; GO;

D O I：

10.1021/ml2002604

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.

引用

页码：216 / 221

页数：6

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