Medicinal chemistry of hERG optimizations: Highlights and hang-ups
Medicinal chemistry of hERG optimizations: Highlights and hang-ups
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DOI：
10.1021/jm060379l
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发表时间：
2006-08-24
影响因子：
7.3
通讯作者：
Wishart, Grant
中科院分区：
文献类型：
--
作者：
Jamieson, Craig;Moir, Elizabeth M.;Wishart, Grant
近年来，由于心电图上Q波开始和T波结束之间的时间延长(QT间期)，包括舍替多尔、格列帕沙星和特非那定在内的上市药物被停用，这促使人们做出相当大的努力，试图建立这种潜在致命现象的分子基础。在大多数情况下，那些延长QT间期并导致尖端扭矩(Tdpa)的化学物质优先与人类乙醚-a-go-go相关基因(HERG)的产物相互作用，HERG是IKR通道的R亚基，负责心脏延迟整流钾电流的快速成分。1-3因此，在整个制药行业，预测QT延长风险的努力一直集中在体外测试表达HERG通道的哺乳动物细胞系的HERG通道活性上。从事Hit-to-Lead和Lead优化活动的药物化学小组遇到了HERG通道的封锁，这是药物发现轨迹上的一个重大障碍。尽管如此，关于克服HERG抑制的战略和战术的信息已经积累了越来越多。本报告对用于测量HERG阻断和QT延长的体内、体外和体内方法进行了简要的总结。以下讨论的目的是总结通过广泛的文献调查确定的规避HERG活动的方法。这些优化被记录为化合物对，这些化合物已经根据减少HERG活性的策略进行了分类。对每一类化合物的性质的审查使一些经验指南得以制定。文中还提出了结论和对今后活动的建议。
In recent years, withdrawal of marketed drugs including sertindole, grepafloxacin, and terfenadine owing to prolongation of the length of time between the start of the Q wave and end of the T wave on an electrocardiogram (QT interval) has prompted considerable effort in trying to establish the molecular basis of this potentially lethal phenomenon. In the majority of cases, those chemical entities that prolong the QT interval and lead to torsades de pointes (TdPa) preferentially interact with a product of the human ether-a-go-go related gene (hERG), the R-subunit of IKr channels responsible for the rapid component of the delayed rectifier potassium current in the heart. 1-3 Consequently, throughout the pharmaceutical industry efforts to predict QT prolongation risk have been focused on assays testing in vitro hERG channel activity in mammalian cell lines expressing the hERG channel. Medicinal chemistry groups engaged in both hit-to-lead and lead optimization activities have encountered blockade of the hERG channel as a significant hurdle along the drug discovery trajectory. Despite this, an increasing body of information has been accumulated on the strategy and tactics for overcoming inhibition of hERG. A brief summary of the in silico, in vitro, and in vivo approaches employed to measure blockade of hERG and QT prolongation is detailed in this report. The purpose of the following discussion is to summarize the approaches engaged to circumvent activity at hERG, identified through an extensive literature survey. The optimizations are recorded as pairs of compounds, which have been categorized in terms of the tactics employed to diminish hERG activity. Examination of the properties of the compounds within each category has enabled formulation of some empirical guidelines. Conclusions and recommendations for future activities are also presented.