GS-967 and eleclazine (GS-6615) are novel sodium channel inhibitors exhibiting antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current (I_NaL). Here, we took advantage of a throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (I_NaP) recorded from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We compared GS-967 and eleclazine to the antiarrhythmic drug lidocaine, the prototype I_NaL inhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. In human induced pluripotent stem cell-derived cardiomyocytes, GS-967 and eleclazine caused a reduction of I_NaP in a frequency-dependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB of I_NaP (IC₅₀=0.07 and 0.6 μM, respectively) than ranolazine (7.8 μM), lidocaine (133.5 μM) and lacosamide (158.5 μM). In addition, GS-967 and eleclazine exerted more potent effects on slow inactivation and recovery from inactivation compared to the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the significantly higher association rates (K_ON) and moderate unbinding rate (K_OFF) of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.

中文翻译：

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GS-967和Eleclazine阻断人类诱导的多能干细胞衍生的心肌细胞中的钠通道

GS-967和eleclazine（GS-6615）是在各种体外和体内模型中均表现出抗心律失常作用的新型钠通道抑制剂。抗心律不齐的机制已归因于优先抑制晚期钠电流（I _NaL）。在这里，我们利用了吞吐量自动电生理平台（SyncroPatch 768PE）来研究GS-967和依来克嗪对人类诱导的多能干细胞（hiPSC）衍生的心肌细胞记录的钠电流峰值（I _NaP）的分子药理作用。我们将GS-967和eleclazine与抗心律不齐药物利多卡因（原型I _{NaL）进行了比较}抑制剂雷诺嗪，以及缓慢失活的增强药物拉考酰胺。在人诱导的多能干细胞衍生的心肌细胞中，GS-967和伊来那嗪以与使用依赖的阻滞（UDB）一致的频率依赖性方式导致I _NaP降低。与雷诺嗪（7.8μM），利多卡因（133.5μM）和拉考酰胺（158.5μM）相比，GS-967和伊来嗪具有相似的功效，但诱发了更强的I _NaP UDB （IC _50分别为0.07和0.6μM）。此外，与我们测试的其他钠通道阻滞药物相比，GS-967和伊曲嗪对缓慢的失活和从失活中恢复的作用更大。GS-967和eleclazine的UDB效能更高是由于显着更高的缔合率（K这两种带有钠通道的化合物的_ON（开）和中等的解键速率（K _OFF）。我们建议大量的UDB有助于观察到的GS-967和eleclazine的抗心律不齐功效。