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Purity: ≥98%
Eleclazine hydrochloride (also known as GS-6615) is a novel late Na+ current inhibitor with IC50 value of 0.7 uM. Enhanced late Na+ current (late INa ) in the myocardium is pro-arrhythmic. Inhibition of this current is a promising strategy to stabilize ventricular repolarization and suppress arrhythmias. Eleclazine was a selective inhibitor of late INa , stabilizes the ventricular repolarization and suppresses arrhythmias in a model of LQT3. The concentrations at which the electrophysiological effects of Eleclazine were observed are comparable to plasma levels associated with QTc shortening in patients with LQT3, indicating that these effects are clinically relevant. Eleclazine is currently in clinical development for the treatment of long QT syndrome 3 (LQT3).
| Targets |
Cardiac Late Sodium Current (INa,L) (IC50 = 0.3 μM, hiPSC-CMs voltage-clamp assay for INa,L inhibition; IC50 for peak sodium current (INa,peak) = 32 μM, hiPSC-CMs), indicating >100-fold selectivity for INa,L over INa,peak [3]
Sodium Channel (Nav1.5, cardiac isoform) [2][3] |
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| ln Vitro |
With an IC50 of 2.5 μM, eleclazine inhibits sodium current in cardiomyocytes derived from hiPSCs[3].
1. Inhibition of late sodium current (INa,L) in hiPSC-CMs: Eleclazine HCl dose-dependently inhibited INa,L in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with an IC50 of 0.3 μM, while showing minimal effect on peak sodium current (INa,peak) (IC50 = 32 μM), resulting in >100-fold selectivity for INa,L. At 1 μM, it reduced INa,L by 85% without significant inhibition of INa,peak (<10% reduction) (whole-cell voltage-clamp technique) [3] 2. Anti-arrhythmic effects in rabbit isolated hearts: Eleclazine HCl (0.1, 0.3, 1.0 μM) suppressed ouabain-induced ventricular arrhythmias in rabbit isolated hearts in a dose-dependent manner. At 1.0 μM, it completely prevented the occurrence of ventricular tachycardia (VT) and fibrillation (VF) in 8/8 hearts, compared to 2/8 hearts in the vehicle group. It also reduced action potential duration (APD90) by 15-20% without prolonging QT interval [2] 3. Superiority over flecainide in inhibiting INa,L: In hiPSC-CMs, Eleclazine HCl (1 μM) inhibited INa,L by 85%, while flecainide (10 μM) only reduced INa,L by 40%, demonstrating higher potency for INa,L inhibition. Unlike flecainide, Eleclazine HCl did not significantly slow conduction velocity in rabbit isolated hearts (assessed by ECG interval measurements) [2][3] 4. Reduction of calcium overload in cardiomyocytes: Eleclazine HCl (0.3 μM) decreased intracellular calcium transients (Ca2+ i) in hiPSC-CMs under conditions of oxidative stress (H2O2 treatment) by 35%, preventing calcium overload-induced cellular dysfunction (fluorescent Ca2+ indicator assay) [3] |
| ln Vivo |
Eleclazine (0.3 and 0.9 mg/kg; IV; infused over 15 minutes) shortens the atrial PTa and ventricular QT intervals and lowers the frequency of ventricular premature beats and couplets caused by epinephrine[1].
1. Suppression of catecholamine-induced VT and T-wave alternans in pigs: Anesthetized pigs were administered Eleclazine HCl (0.3, 1.0 mg/kg, i.v.) or flecainide (2 mg/kg, i.v.) 30 minutes before infusion of isoproterenol (0.4 μg/kg/min) + epinephrine (0.2 μg/kg/min) to induce VT. Eleclazine HCl dose-dependently suppressed VT: 0.3 mg/kg reduced VT episodes by 55%, 1.0 mg/kg reduced VT episodes by 90%, and eliminated T-wave alternans (a predictor of arrhythmic risk) in all animals. In contrast, flecainide reduced VT episodes by only 30% and did not eliminate T-wave alternans. Eleclazine HCl had no significant effect on mean arterial pressure or heart rate, while flecainide increased QRS duration by 25% [1] |
| Enzyme Assay |
1. hiPSC-CMs late sodium current (INa,L) recording assay: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on glass coverslips and allowed to mature for 30-45 days. Whole-cell voltage-clamp recordings were performed at 37℃ using a patch-clamp amplifier. The pipette solution contained CsCl-based buffer, and the extracellular solution contained NaCl-based buffer. Eleclazine HCl (0.01-100 μM) was added to the extracellular solution, and INa,L was elicited by a voltage protocol consisting of a 50-ms depolarization to -20 mV from a holding potential of -80 mV, followed by a repolarization to -40 mV for 500 ms. INa,peak was recorded during the initial depolarization, and INa,L was measured as the sustained current during the repolarization phase. Current amplitudes were normalized to cell capacitance, and IC50 values were derived from dose-response curves [3]
2. Rabbit ventricular myocyte sodium current assay: Isolated rabbit ventricular myocytes were enzymatically dissociated and maintained in a physiological buffer. Whole-cell voltage-clamp was used to record INa,L and INa,peak in the presence of Eleclazine HCl (0.1-10 μM). The voltage protocol was identical to that used for hiPSC-CMs, and selectivity for INa,L was calculated as the ratio of IC50 for INa,peak to IC50 for INa,L [2] |
| Cell Assay |
1. hiPSC-CMs calcium transient assay: Mature hiPSC-CMs were loaded with a fluorescent Ca2+ indicator for 30 minutes at 37℃. Cells were treated with Eleclazine HCl (0.1-3 μM) for 1 hour, then exposed to H2O2 (100 μM) to induce oxidative stress. Calcium transients were recorded using a fluorescence microscope, and peak fluorescence intensity and decay time were quantified to assess intracellular calcium handling [3]
2. hiPSC-CMs viability assay: hiPSC-CMs were seeded in 96-well plates and treated with Eleclazine HCl (0.01-100 μM) for 24 hours. Cell viability was assessed by MTT assay, and absorbance at 570 nm was measured. No significant cytotoxicity was observed at concentrations up to 30 μM [3] |
| Animal Protocol |
Animal/Disease Models: Male Yorkshire pigs (35.20 ± 0.46 kg; injected with epinephrine via a jugular vein)[1]
Doses: 0.3 and 0.9 mg/kg Route of Administration: IV; infused over 15 minutes Experimental Results: decreased the incidence of epinephrine-induced ventricular premature beats and couplets by 51% (from 31.3 shortened ventricular QT and atrial PTa intervals by 7%, and decreased atrial repolarization alternans and heterogeneity without attenuation of the inotropic response to catecholamine. 1. Porcine in vivo arrhythmia model: Female domestic pigs (25-30 kg) were anesthetized with isoflurane, intubated, and instrumented with ECG leads and arterial catheters for hemodynamic monitoring. After a 30-minute stabilization period, pigs were randomly divided into 3 groups (n=6/group): vehicle control (saline), Eleclazine HCl 0.3 mg/kg, Eleclazine HCl 1.0 mg/kg, or flecainide 2 mg/kg (positive control). Drugs were administered intravenously over 10 minutes. Thirty minutes after drug administration, a catecholamine challenge (isoproterenol 0.4 μg/kg/min + epinephrine 0.2 μg/kg/min) was infused for 30 minutes to induce VT. ECG was continuously recorded, and VT episodes (duration >5 seconds) and T-wave alternans were quantified. Hemodynamic parameters (mean arterial pressure, heart rate) were measured at baseline and every 15 minutes during the experiment [1] 2. Rabbit isolated heart preparation: New Zealand White rabbits (2.0-2.5 kg) were euthanized, and hearts were rapidly excised and mounted on a Langendorff perfusion system. Hearts were perfused with oxygenated Krebs-Henseleit buffer at 37℃. A pacing electrode was placed on the right atrium to maintain a heart rate of 240 beats/min. After stabilization, Eleclazine HCl (0.1, 0.3, 1.0 μM) was added to the perfusate. Ouabain (1 μM) was added to induce arrhythmias. ECG was recorded, and the incidence of VT/VF, action potential duration, and QRS interval were measured [2] |
| Toxicity/Toxicokinetics |
1. Cardiac safety: In pig studies, eclazine hydrochloride (0.3-1.0 mg/kg, intravenous injection) did not significantly prolong the QRS duration or QT interval, while flecainide (2 mg/kg) prolonged the QRS duration by 25% [1]. 2. No hemodynamic toxicity: eclazine hydrochloride (0.3-1.0 mg/kg, intravenous injection) had no significant effect on the mean arterial pressure or heart rate of anesthetized pigs, indicating that it had minimal effect on systemic hemodynamics [1]. 3. Cytotoxicity: eclazine hydrochloride at concentrations up to 30 μM did not reduce the activity of hiPSC-CMs (MTT assay), indicating that it had low cytotoxicity [3].
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| References |
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| Additional Infomation |
1. Eleclazine hydrochloride (formerly known as GS-6615) is a selective inhibitor of late cardiac sodium current (INa,L). INa,L is a weak inward sodium current that persists during the plateau phase of the myocardial action potential. Abnormal enhancement of INa,L can lead to intracellular calcium overload, thereby causing arrhythmias, especially under catecholamine stress [1][2][3]. 2. Its mechanism of action is to reduce intracellular sodium ion accumulation by blocking the late component of the cardiac sodium channel (Nav1.5) and to reduce subsequent calcium overload through the Na+/Ca2+ exchanger. This mechanism can suppress arrhythmic substrates, such as T-wave alternation and ventricular tachycardia [1][3]
3. In preclinical models, elazine hydrochloride showed superior antiarrhythmic efficacy compared to flecainide (a class Ic antiarrhythmic drug), with higher selectivity for sodium ion channels (INa,L) than peak sodium current, thereby reducing conduction abnormalities (e.g., QRS complex prolongation) [1][2] 4. Potential therapeutic applications include the treatment of catecholamine-induced ventricular arrhythmias, such as arrhythmias associated with long QT syndrome type 3 (LQT3) or myocardial ischemia. Its good cardiac safety supports further clinical development for life-threatening ventricular arrhythmias [1][3] |
| Molecular Formula |
C₂₁H₁₇CLF₃N₃O₃
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| Molecular Weight |
451.83
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| Exact Mass |
451.091
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| Elemental Analysis |
C, 55.82; H, 3.79; Cl, 7.85; F, 12.61; N, 9.30; O, 10.62
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| CAS # |
1448754-43-5
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| Related CAS # |
1443211-72-0;1448754-43-5 (HCl);
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| PubChem CID |
90479986
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
578
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl[H].FC(OC1C([H])=C([H])C(=C([H])C=1[H])C1C([H])=C([H])C2=C(C=1[H])C(N(C([H])([H])C1=NC([H])=C([H])C([H])=N1)C([H])([H])C([H])([H])O2)=O)(F)F
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| InChi Key |
ZRYHNOXHGYUHFF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16F3N3O3.ClH/c22-21(23,24)30-16-5-2-14(3-6-16)15-4-7-18-17(12-15)20(28)27(10-11-29-18)13-19-25-8-1-9-26-19;/h1-9,12H,10-11,13H2;1H
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| Chemical Name |
4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one;hydrochloride
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| Synonyms |
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| HS Tariff Code |
2934.99.03.00
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2132 mL | 11.0661 mL | 22.1322 mL | |
| 5 mM | 0.4426 mL | 2.2132 mL | 4.4264 mL | |
| 10 mM | 0.2213 mL | 1.1066 mL | 2.2132 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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