GS967 _Sodium Channel 抑制剂 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGS967Cat. No.: HY-12593CAS No.: 1262618-39-2分式: CHFNO分量: 347.22作靶点: Sodium Channel作通路: Membrane Transporter/Ion Channel储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性数据体外实验 DMSO : 50 mg/mL (144.00 mM; N

2、eed ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 2.8800 mL 14.4001 mL 28.8002 mL5 mM 0.5760 mL 2.8800 mL 5.7600 mL10 mM 0.2880 mL 1.4400 mL 2.8800 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加助溶剂(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根

3、据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (7.20 mM); Suspended solution; Need ultrasonic2. 请依序添加每种溶剂： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (7.20 mM); Clear solutionBIOLOGICAL ACTIVITY1/3 Master of Small Molecules 您边的抑制剂师

4、www.MedChemE物活性 GS967 (GS-458967)有效地选择性的脏晚期钠电流抑制剂（late INa），在室肌细胞和脏中的IC50值分别为0.13和0.21 M。IC50 & Target IC50: 0.13 M (late INa , ventricular myocytes )and 0.21 M (late INa , isolated hearts) 1体外研究 GS967 (10, 100, 300 nM) completely attenuates the effect of ATX-II (10 nM) to increase action potentiald

5、uration (APD) and APD variability in ventricular myocytes, with an apparent IC50 value of -10 nM anddecreased the beat-to-beat variability of APD 1.体内研究 GS967 prevents and reverses proarrhythmic effects of the late INa enhancer ATX-II and the IKr inhibitor E-4031. GS967 significantly attenuates the

6、proarrhythmic effects of methoxamine 1 clofilium and suppressedischemia-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 M) thanranolazine (16 M) and lidocaine (17 M). GS

7、967 is found to exert these same effects on a prototypical longQT syndromemutation (delKPQ) 2. GS967 prevents ischemia-induced increases in alternans in the leftatrium and left ventricle. GS967 reduces ischemia-induced increases in depolarization heterogeneity andrepolarizationheterogeneity. GS967 d

8、oes not alter heart rate, arterial blood pressure, PR and QT intervals, orQRS duration, but it mildly decreased contractility during ischemia, which was consistent with late INainhibition 3.PROTOCOLAnimal Rats: Ventricular tachycardia or fibrillation are induced either by local aconitine injection (

9、50 g) in the leftAdministration 12 ventricular muscle of adult male rats or by arterial perfusion of 0.1 mM hydrogen peroxide in aged male rats.The left ventricular epicardial surface of the isolated-perfused hearts is optically mapped using fluorescentvoltage-sensitive dye, and microelectrode recor

10、dings of action potentials are made adjacent to the aconitineinjection site. The suppressive and preventive effects of GS967 (1 M) against EAD/DAD-mediatedventricular tachycardia or fibrillation are then determined 2.Rabbits: To determine the effect of GS967 on the inducibility of TdP by clofilium i

11、n the presence ofmethoxamine, rabbits are first treated with either vehicle or GS967 (in randomized manner) given as a 60 g/kg bolus, followed by a 16 g/kg/min infusion that is maintained for the duration of an experiment. After 10minutes, methoxamine is infused intravenously at 15 g/kg/min, followe

12、d 10 minutes later by clofilium at 100nmol/kg/min. The incidences of premature ventricular contractions (PVCs), ventricular tachycardia (VT;defined as three or more consecutive abnormal beats), and TdP are determined from the ECG recordings 1.MCE has not independently confirmed the accuracy of these

13、 methods. They are for reference only.户使本产品发表的科研献 Br J Pharmacol. 2018 Dec;175(23):4325-4337. Circ Arrhythm Electrophysiol. 2017 Mar;10(3). pii: e004331. Cardiovasc Drugs Ther. 2018 Oct;32(5):413-425. J Cardiovasc Pharmacol. 2016 Oct;68(4):269-279. bioRxiv. 2019 Jan.2/3 Master of Small Molecules 您边的

14、抑制剂师www.MedChemESee more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Belardinelli L, et al. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. JPharmacol Exp Ther. 2013 Jan;344(1):23-32.2. Potet F, et al. Use-Dependent Block

15、of Human Cardiac Sodium Channels by GS967. Mol Pharmacol. 2016 Jul;90(1):52-60.3. Bonatti R, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricularrepolarization alternans and ECG heterogeneity. Heart Rhythm. 2014 Oct;11(10):1827-35.4. Wei X, et al. Pre- and Delayed Treatments With Ranolazine Ameliorate Ventricular Arrhythmias and Nav1.5 Downregulation inIschemic/Reperfused Rat Hearts. J Cardiovasc P