首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Identification and Characterization of a Compound That Protects Cardiac Tissue from Human Ether-à-go-go-related Gene (hERG)-related Drug-induced Arrhythmias
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Identification and Characterization of a Compound That Protects Cardiac Tissue from Human Ether-à-go-go-related Gene (hERG)-related Drug-induced Arrhythmias

机译:化合物的鉴定和表征该化合物可保护心脏组织免于人类以去转相关基因(hERG)相关的药物引起的心律失常

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摘要

The human Ether-à-go-go-related gene (hERG)-encoded K+ current, IKr is essential for cardiac repolarization but is also a source of cardiotoxicity because unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes IKr block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC70 of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC50 of dofetilide from 38.7 to 76.3 nm. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors.
机译:人类以太相关基因(hERG)编码的K + 电流IKr对于心脏复极是必不可少的,但也是心脏毒性的来源,因为各种药物意外地抑制hERG可能导致心律不齐和心源性猝死。我们假设通过已知的hERG拮抗剂减少IKr阻滞的小分子将构成预防hERG相关心律失常和促进药物发现的第一步。使用高通量分析,我们筛选了化合物库中增加dofetilide(一种充分表征的hERG阻断剂)IC70的药物。具有所需活性的一种化合物VU0405601被进一步表征。在孤立的Langendorff灌注兔心脏中,光学成像显示,用VU0405601预处理后,多芬利特引起的心律不齐有所减少。在稳定的hERG-HEK细胞中进行膜片钳分析表明对电流幅度,失活和失活有影响。 VU0405601将多非利特的IC50从38.7 nm提高到76.3 nm。 VU0405601主要通过减少失活来从细胞外方面缓解hERG阻滞剂的作用,而大多数临床相关的hERG抑制剂则作用于内孔部位。 VU0405601周围的构效关系确定了3-吡啶基和萘啶环系统是关键的结构成分,对于防止多种抑制剂抑制hERG具有重要意义。这些发现表明,可以设计小分子以降低hERG对抑制剂的敏感性。

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