GS967inhibitor of cardiac late sodium current CAS# 1262618-39-2 |
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| Cas No. | 1262618-39-2 | SDF | Download SDF |
| PubChem ID | 58118983 | Appearance | Powder |
| Formula | C14H7F6N3O | M.Wt | 347.22 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 50 mg/mL (144.00 mM; Need ultrasonic) | ||
| Chemical Name | 6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine | ||
| SMILES | C1=CC(=CC=C1C2=CN3C(=NN=C3C(F)(F)F)C=C2)OC(F)(F)F | ||
| Standard InChIKey | FEVBKJITJDHASC-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C14H7F6N3O/c15-13(16,17)12-22-21-11-6-3-9(7-23(11)12)8-1-4-10(5-2-8)24-14(18,19)20/h1-7H | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | 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.In Vitro: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]. References: | |||||
GS967 Dilution Calculator
GS967 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.88 mL | 14.4001 mL | 28.8002 mL | 57.6004 mL | 72.0005 mL |
| 5 mM | 0.576 mL | 2.88 mL | 5.76 mL | 11.5201 mL | 14.4001 mL |
| 10 mM | 0.288 mL | 1.44 mL | 2.88 mL | 5.76 mL | 7.2 mL |
| 50 mM | 0.0576 mL | 0.288 mL | 0.576 mL | 1.152 mL | 1.44 mL |
| 100 mM | 0.0288 mL | 0.144 mL | 0.288 mL | 0.576 mL | 0.72 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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GS967 is a potent, selective and novel inhibitor of cardiac late sodium current (late INa) with IC50=0.13 μM in ventricular myocytes and IC50=0.21μM in isolated hearts. [1]
When Na+ channels in myocytes fail to inactivate after opening, Na+ influx continues throughout the AP plateau. The resulting Na+ current (INa) is referred to as late INa. Its magnitude is increased in many pathologic conditions, such as in the failing and/or ischemic heart, in the heart exposed to oxidative stress, and in hearts of patients with congenital long QT3 syndromes. [1]
In rabbit isolated ventricular myocytes, inhibition of peak INa by GS967 is in a concentration- and voltage-dependent manner with minimal use-dependent, it also decreases the Na+ and Ca2+ overload. In rabbit-isolated heart, GS967 abolishes TdP Induced by ATX-II or E-4031. [1]
In anesthetized rabbit, GS967 reduces MAPD90 but did not alter cardiac conduction time; it also prevents the Induction of arrhythmic activity and TdP by clofilium and decreases the Incidence of ischemia-Induced arrhythmias. [1]
Reference:
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 Pharmacol Exp
Ther. 2013 Jan;344(1):23-32.
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Use-Dependent Block of Human Cardiac Sodium Channels by GS967.[Pubmed:27136942]
Mol Pharmacol. 2016 Jul;90(1):52-60.
GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (GS967) is a recently described, novel, sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current. However, there has been no reported systematic investigation of the effects of this compound on isolated sodium channels. Here, we examined the effects of GS967 on peak (INaP) and late (INaL) sodium current recorded from cells that heterologously expressed human cardiac voltage-gated sodium channel, the principle cardiac sodium channel. As previously described, we observed that GS967 exerted tonic block of INaL (63%) to a significantly greater extent than INaP (19%). However, GS967 also caused a reduction of INaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evoked more potent UDB of INaP (IC50 = 0.07 microM) than ranolazine (16 microM) and lidocaine (17 microM). Use-dependent block was best explained by a significant slowing of recovery from fast and slow inactivation with a significant enhancement of slow inactivation in the presence of GS967. Furthermore, GS967 was found to exert these same effects on a prototypical long QT syndrome mutation (delKPQ). An engineered mutation at an interaction site for local anesthetic agents (F1760A) partially attenuated the effect of GS967 on UDB, but had no effect on tonic INaL block. We conclude that GS967 is a preferential inhibitor of INaL, but it also exerts previously unreported strong effects on slow inactivation and recovery from inactivation, resulting in substantial UDB that is not entirely dependent on a known interaction site for local anesthetic agents.
