GS967 is a potent and selective inhibitor of late sodium current (late INa) in ventricular myocytes and isolated hearts with IC50 values of 0.13 and 0.21µM, respectively [1]. GS967 can induce a hyperpolarized shift of steady-state channel inactivation and slowe both recovery from fast inactivation and onset of slow inactivation[2]. GS967 has been widely used in various models to block cardiac sodium channels, exhibiting antiarrhythmic effects [3].
In vitro, GS967 treatment inhibited peak sodium current (INaP) with use-dependent block (UDB) in cardiomyocytes derived from pluripotent stem cells within 400milliseconds, with an IC50 value of 0.07μM[4].
In vivo, GS967 treatment via oral administration at a dose of 1.5mg/kg/day for 38 days significantly prolonged the survival rate of Scn1a+/− mice and reduced seizure frequency[5]. For two consecutive days, administering a daily dose of 1.5mg/kg/day of GS967 significantly reduced the seizure frequency in Scn2aQ54 mice and prevented the loss of pulmonary ganglion neurons[6]. Oral administration of 1mg/kg/day dose of GS967 for 5 consecutive weeks significantly reduced the left ventricular mass and lung edema of Dahl salt-sensitive (DSS) rats on a high-salt diet, without affecting blood pressure or left ventricular contractility[7].
References:
[1] Belardinelli L, Liu G, Smith-Maxwell C, et al. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias[J]. The Journal of pharmacology and experimental therapeutics, 2013, 344(1): 23-32.
[2] Baker E M, Thompson C H, Hawkins N A, et al. The novel sodium channel modulator GS‐458967 (GS 967) is an effective treatment in a mouse model of SCN 8A encephalopathy[J]. Epilepsia, 2018, 59(6): 1166-1176.
[3] Vos M A, Houtman M, Antoons G, et al. GS967, By Blocking the Late Sodium Current (INaL), Has Strong Action Potential–Stabilizing Properties in Isolated Remodeled Ventricular Canine Cells[J]. Heart Rhythm, 2013, 10(11): 1742.
[4] Potet F, Egecioglu D E, Burridge P W, et al. GS-967 and eleclazine block sodium channels in human induced pluripotent stem cell–derived cardiomyocytes[J]. Molecular pharmacology, 2020, 98(5): 540-547.
[5] Anderson L L, Hawkins N A, Thompson C H, et al. Unexpected efficacy of a novel sodium channel modulator in Dravet syndrome[J]. Scientific reports, 2017, 7(1): 1682.
[6] Anderson L L, Thompson C H, Hawkins N A, et al. Antiepileptic activity of preferential inhibitors of persistent sodium current[J]. Epilepsia, 2014, 55(8): 1274-1283.
[7] Chi L, Belardinelli L, Zeng A, et al. Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2016, 310(10): H1313-H1320.
GS967是一种强效、选择性的晚期钠电流抑制剂，在心室肌细胞和离体心脏中的IC50值分别为0.13μM和0.21μM[1]。GS967可通过诱导钠通道稳态失活的超极化偏移，延缓快速失活后的恢复过程并减缓慢失活的发生[2]。GS967已在多种模型中广泛应用于心脏钠通道阻断，展现出抗心律失常作用[3]。
在体外，GS967能在400毫秒内以使用依赖性阻滞方式(UDB)抑制多能干细胞来源心肌细胞的峰值钠电流(INaP)，IC50值为0.07μM[4]。
在体内，连续38天口服1.5mg/kg/day剂量的GS967可显著提高Scn1a+/-基因缺陷小鼠的存活率并降低癫痫发作频率[5]。连续2天每日给予1.5mg/kg剂量的GS967，能有效减少Scn2aQ54小鼠的癫痫发作次数，并预防肺内神经元丢失[6]。对高盐饮食的Dahl盐敏感性(DSS)大鼠连续5周每日口服1mg/kg/day剂量的GS967，可显著减轻左心室质量及肺水肿程度，且不影响血压或左心室收缩功能[7]。