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| Targets |
JTV-519 has multiple targets in cardiac and skeletal muscle. It acts as a Ca2+-dependent blocker of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) and as a partial agonist of ryanodine receptors (RyRs, specifically RyR1 and RyR2). Through these actions, JTV-519 modulates calcium handling in striated muscle cells, preventing abnormal Ca2+ release from the sarcoplasmic reticulum that can lead to arrhythmias and heart failure. It also inhibits annexin V-dependent Ca2+ influx into large unilamellar vesicles.
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| ln Vitro |
In a dose-dependent manner, JTV-519 (K201) blocks the inward Ca2+ migration into large unilamellar vesicles (LUV) produced by annexin V. When 50 nM annexin V and 400 μM Ca2+ are present, 3 μM JTV-519 significantly inhibits the flow of Ca2+ caused by annexin V, and 25% inhibition is attained at 25 μM K201[2].
In vitro, JTV-519 (K201) inhibits inward Ca2+ movement into large unilamellar vesicles (LUV) caused by annexin V in a dose-dependent manner, demonstrating a direct effect on Ca2+ flux at the membrane level. The compound acts as a Ca2+-dependent blocker of SERCA and a partial agonist of RyRs. JTV-519 stabilizes the closed state of RyR2 channels, preventing diastolic Ca2+ leak from the sarcoplasmic reticulum, which is a key pathological mechanism in heart failure and catecholaminergic polymorphic ventricular tachycardia (CPVT). |
| ln Vivo |
In CLP mice, JTV-519 (0.5 mg/kg/h, intravenously, two hours before to surgery) improves cardiac function; in comparison to CLP animals not receiving JTV-519 treatment, the fractional shortening (FS) and ejection fraction (EF) are significantly higher[3].
In vivo, JTV-519 has demonstrated antiarrhythmic and cardioprotective properties. The compound was developed by Japan Tobacco as an antiarrhythmic agent and was advanced to Phase II clinical trials for the potential treatment of atrial fibrillation. JTV-519 protects the heart from ischemia-reperfusion injury and prevents the development of heart failure in animal models by reducing aberrant Ca2+ release from the sarcoplasmic reticulum and improving cardiac contractility. A Phase II trial was initiated but subsequently terminated. |
| Enzyme Assay |
Not applicable. The primary mechanism of JTV-519 involves modulation of Ca2+ handling proteins in a cellular context rather than binding to a soluble target. For biochemical characterization, JTV-519 activity can be assessed using purified sarcoplasmic reticulum vesicles (SR vesicles) isolated from cardiac or skeletal muscle. SR vesicles are incubated with varying concentrations of JTV-519 (0.1-100 uM) in the presence of ATP, and Ca2+ uptake or release is measured using fluorescent Ca2+ indicators (e.g., Fluo-4, Fura-2) or 45Ca2+ radiometric methods to quantify SERCA inhibition and RyR modulation.
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| Cell Assay |
A standard cellular assay for JTV-519 activity uses isolated adult rat or rabbit ventricular myocytes. Myocytes are loaded with a Ca2+-sensitive fluorescent dye (e.g., Fluo-4 AM or Fura-2 AM) and placed on an inverted microscope. Cells are electrically stimulated at 0.5-2 Hz to induce regular contractions. JTV-519 (0.1-10 uM) is applied via perfusion, and systolic and diastolic Ca2+ levels are measured by fluorescence imaging. The reduction of aberrant Ca2+ waves and sparks is quantified. Alternatively, RyR2-mediated Ca2+ release is measured in permeabilized myocytes using confocal microscopy.
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| Animal Protocol |
Animal/Disease Models: Wild type male C57BL/6 mice weighing 18-22g with polymicrobial sepsis produced by cecal ligation and puncture (CLP)[3]
Doses: 0.5 mg/kg/h Route of Administration: Applied intraperitoneally (ip) 2 h before the surgery Experimental Results: Improved cardiac function, where the EF and FS were Dramatically increased. In an in vivo protocol, JTV-519 is tested in a rodent model of cardiac ischemia-reperfusion (I/R) injury. Male Sprague-Dawley rats are anesthetized, and the left anterior descending (LAD) coronary artery is ligated for 30-45 minutes to induce ischemia, followed by reperfusion for 2-24 hours. JTV-519 is administered intravenously (e.g., 0.1-1 mg/kg) or intraperitoneally (e.g., 1-10 mg/kg) prior to ischemia or at the onset of reperfusion. Infarct size is measured by triphenyltetrazolium chloride (TTC) staining. Arrhythmia severity is assessed by ECG recording, and cardiac function is measured by echocardiography. Cardioprotection is indicated by reduced infarct size, fewer arrhythmias, and improved ejection fraction. |
| ADME/Pharmacokinetics |
JTV-519 was advanced to Phase II clinical trials as an antiarrhythmic agent, indicating acceptable pharmacokinetic properties. The compound is orally bioavailable and distributes to cardiac tissue. Specific PK parameters (t1/2, Cmax, oral bioavailability) from preclinical and clinical studies are not provided in the available references, but the progression to Phase II suggests adequate exposure for once- or twice-daily oral dosing. The hemifumarate salt formulation improves solubility and stability for pharmaceutical use.
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| Toxicity/Toxicokinetics |
JTV-519 was progressed to Phase II clinical trials for the potential treatment of atrial fibrillation, indicating an acceptable preclinical safety profile. Common adverse effects related to its mechanism of action (modulation of cardiac Ca2+ handling) may include hypotension or bradycardia. In preclinical models, JTV-519 was well-tolerated at cardioprotective doses. However, the Phase II study was terminated, though the specific reason for termination is not provided in the available references. Safety findings in the terminated trial may not be publicly available.
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| References |
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| Additional Infomation |
JTV-519 (K201) is a 1,4-benzothiazepine derivative that is structurally related to the L-type calcium channel blocker diltiazem but has a distinct mechanism involving RyR2 and SERCA modulation. The compound was developed by Japan Tobacco as an antiarrhythmic agent and advanced to Phase II clinical trials for the potential treatment of atrial fibrillation. JTV-519 has also been studied for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), a genetic arrhythmia syndrome caused by RyR2 mutations. The compound is also known as JTV-519 free base (CAS 145903-06-6), and the hemifumarate salt (CAS 1435938-25-2) is used to improve solubility and formulation. JTV-519 is a valuable pharmacological tool for studying the role of RyR2 and SERCA in cardiac calcium handling, arrhythmogenesis, and heart failure. Researchers should note that the compound has RyR2-stabilizing properties distinct from other RyR modulators and may have off-target effects on other ion channels at higher concentrations.
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| Molecular Formula |
C25H32N2O2S.1/2C4H4O4
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|---|---|
| Molecular Weight |
482.64
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| Exact Mass |
964.447
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| CAS # |
1435938-25-2
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| Related CAS # |
JTV-519;1038410-88-6;JTV-519 free base;145903-06-6
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| PubChem CID |
91885458
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
68
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| Complexity |
650
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=CC2=C(C=C1)SCCN(C2)C(=O)CCN3CCC(CC3)CC4=CC=CC=C4.COC1=CC2=C(C=C1)SCCN(C2)C(=O)CCN3CCC(CC3)CC4=CC=CC=C4.C(=C/C(=O)O)\C(=O)O
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| InChi Key |
MNAIJOCDPCXVEY-WXXKFALUSA-N
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| InChi Code |
InChI=1S/2C25H32N2O2S.C4H4O4/c2*1-29-23-7-8-24-22(18-23)19-27(15-16-30-24)25(28)11-14-26-12-9-21(10-13-26)17-20-5-3-2-4-6-20;5-3(6)1-2-4(7)8/h2*2-8,18,21H,9-17,19H2,1H3;1-2H,(H,5,6)(H,7,8)/b;;2-1+
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| Chemical Name |
3-(4-benzylpiperidin-1-yl)-1-(7-methoxy-3,5-dihydro-2H-1,4-benzothiazepin-4-yl)propan-1-one;(E)-but-2-enedioic acid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
DMSO: 100 mg/mL (207.19 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0719 mL | 10.3597 mL | 20.7194 mL | |
| 5 mM | 0.4144 mL | 2.0719 mL | 4.1439 mL | |
| 10 mM | 0.2072 mL | 1.0360 mL | 2.0719 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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