| Bioactivity | GS967 (GS-458967) is a potent, and selective inhibitor of cardiac late sodium current (late INa ) with IC50 values of 0.13 and 0.21 μM for ventricular myocytes and isolated hearts, respectively. | ||||||||||||
| Target | IC50: 0.13 μM (late INa , ventricular myocytes )and 0.21 μM (late INa , isolated hearts) | ||||||||||||
| Invitro | GS967 (10, 100, 300 nM) completely attenuates the effect of ATX-II (10 nM) to increase action potential duration (APD) and APD variability in ventricular myocytes, with an apparent IC50 value of ∼10 nM and decreased the beat-to-beat variability of APD[1]. | ||||||||||||
| In Vivo | GS967 prevents and reverses proarrhythmic effects of the late INa enhancer ATX-II and the IKr inhibitor E-4031. GS967 significantly attenuates the proarrhythmic effects of methoxamine 1 clofilium and suppressed ischemia-induced arrhythmias[1]. GS967 causes a reduction of INaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evokes more potent UDB of INaP (IC50=0.07 μM) than ranolazine (16 μM) and lidocaine (17 μM). GS967 is found to exert these same effects on a prototypical long QT syndromemutation (delKPQ)[2]. GS967 prevents ischemia-induced increases in alternans in the left atrium and left ventricle. GS967 reduces ischemia-induced increases in depolarization heterogeneity and repolarizationheterogeneity. GS967 does not alter heart rate, arterial blood pressure, PR and QT intervals, or QRS duration, but it mildly decreased contractility during ischemia, which was consistent with late INa inhibition[3]. | ||||||||||||
| Name | GS967 | ||||||||||||
| CAS | 1262618-39-2 | ||||||||||||
| Formula | C14H7F6N3O | ||||||||||||
| Molar Mass | 347.22 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
| Storage |
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| Reference | [1]. Belardinelli L, et al. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther. 2013 Jan;344(1):23-32. [2]. Wei X, et al. Pre- and Delayed Treatments With Ranolazine Ameliorate Ventricular Arrhythmias and Nav1.5 Downregulation in Ischemic/Reperfused Rat Hearts. J Cardiovasc Pharmacol. 2016 Oct;68(4):269-279. [3]. Potet F, et al. Use-Dependent Block of Human Cardiac Sodium Channels by GS967. Mol Pharmacol. 2016 Jul;90(1):52-60. [4]. Bonatti R, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm. 2014 Oct;11(10):1827-35. |