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Ranolazine 2HCl (known also as Ranolazine diHydrochloride), the diHCl salt of ranolzaine (RS43285; CVT303), is a an anti-angina drug which acts as a potent calcium uptake inhibitor via the sodium/calcium channel, it is used to treat chronic angina. Ranolazine is an anti-ischemic agent that inhibits late sodium current that results in a reduction of Na+ dependent Ca2+ overload. Ranolazine can cause the shift of ATP production towards glucose oxidation, which is due to the fact that more oxygen is required to phosphorylate the same amount of ATP during fatty acid oxidation than carbohydrate oxidation. These studies indicate that Ranolazine also inhibits oxygen consumption and ketogenesis by fatty acids in liver cells.
Physicochemical Properties
| Molecular Formula | C24H33N3O4.2HCL | |
| Molecular Weight | 500.46 | |
| Exact Mass | 499.2 | |
| CAS # | 95635-56-6 | |
| Related CAS # | Ranolazine-d8 dihydrochloride;1219802-60-4;Ranolazine;95635-55-5 | |
| PubChem CID | 71279 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 624.1ºC at 760 mmHg | |
| Melting Point | 222-229.5ºC(lit.) | |
| LogP | 3.86 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 9 | |
| Heavy Atom Count | 33 | |
| Complexity | 531 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | RJNSNFZXAZXOFX-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C24H33N3O4.2ClH/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3;;/h4-10,20,28H,11-17H2,1-3H3,(H,25,29);2*1H | |
| Chemical Name | N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide;dihydrochloride | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| Targets |
Ranolazine 2HCl (RS-43285; CVT-303) primarily targets the late sodium current (INaL) in cardiomyocytes, with an IC50 of 3-10 μM for inhibiting INaL in isolated human ventricular myocytes. It also weakly inhibits carnitine palmitoyltransferase 1 (CPT1, a key enzyme in fatty acid oxidation) with a Ki of ~80 μM, and shows minimal activity against other ion channels (e.g., IC50 >100 μM for hERG/IKr channels) [1] - Ranolazine 2HCl (RS-43285; CVT-303) exhibits moderate inhibition of the sodium-calcium exchanger (NCX) in rat ventricular myocytes, with an EC50 of ~25 μM for reducing NCX-mediated calcium efflux, which contributes to mitigating intracellular calcium overload [3] |
| ln Vitro |
In vitro activity: Ranolazine selectively inhibits late I(Na), reduces [Na(+)](i)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure in myocardial cells. Ranolazine significantly and reversibly shortens the action potential duration (APD) of myocytes stimulated at either 0.5 Hz or 0.25 Hz in a concentration-dependent manner in left ventricular myocytes of dogs. Ranolazine at 5 and 10 mM reversibly shortens the duration of twitch contractions (TC) and abolished the after contraction. Ranolazine is found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying I(NaL). Inhibition of late sodium current (INaL): In isolated human ventricular myocytes, Ranolazine 2HCl (1-30 μM) inhibits INaL in a concentration-dependent manner. At 10 μM, it reduces INaL amplitude by 65±8% without significantly affecting the fast sodium current (INaF) or L-type calcium current (ICaL), confirming selectivity for INaL [1] - Modulation of myocardial energy metabolism: In rat heart mitochondria, Ranolazine 2HCl (10-100 μM) inhibits fatty acid oxidation (FAO) by targeting CPT1. At 30 μM, it reduces FAO rate by 40±6%, while increasing glucose oxidation by 25±5% (measured via radioactive substrate incorporation), shifting myocardial energy substrate utilization toward glucose (a more oxygen-efficient fuel) [3] - Protection against myocardial cell ischemia-reperfusion injury: In HL-1 cardiomyocytes subjected to 1-hour anoxia (ischemia) followed by 2-hour reoxygenation, Ranolazine 2HCl (10 μM) reduces lactate dehydrogenase (LDH) release (a marker of cell necrosis) by 35±7% and maintains ATP levels at 60±5% of normal (vs. 30±4% in vehicle controls). It also decreases intracellular calcium overload (measured via Fura-2 AM staining) by 45±6% [3] - Antiar rhythmic effect in isolated cardiac tissues: In rabbit papillary muscles, Ranolazine 2HCl (5-20 μM) suppresses early afterdepolarizations (EADs) induced by high concentrations of catecholamines. At 20 μM, it eliminates EADs in 80% of preparations, compared to 20% in vehicle controls [2] |
| ln Vivo |
In rats undergoing left anterior descending coronary artery occlusion-reperfusion, ranolazine (bolus injection 10 mg/kg and infusion 9.6 mg/kg/h; bolus injection; for 145 minutes; male Wistar rats) therapy dramatically lowers infarct size and cardiac troponin T release [3]. Efficacy in chronic stable angina (preclinical correlates): In dogs with exercise-induced myocardial ischemia, oral Ranolazine 2HCl (30-100 mg/kg, once daily for 7 days) increases exercise tolerance time (ETT) by 30±5% (100 mg/kg dose) and reduces ST-segment depression (a marker of myocardial ischemia) by 45±8% during exercise, without altering heart rate or blood pressure [1] - Antiar rhythmic activity in rabbits: In anesthetized New Zealand white rabbits, intravenous Ranolazine 2HCl (1, 3, 10 mg/kg) dose-dependently suppresses aconitine-induced ventricular arrhythmias. The 10 mg/kg dose reduces the incidence of ventricular fibrillation (VF) from 80% (vehicle) to 20% and shortens arrhythmia duration from 25±5 minutes to 5±2 minutes [2] - Reduction of myocardial infarct size in rats: In male Sprague-Dawley rats subjected to 30-minute coronary artery ligation (ischemia) followed by 2-hour reperfusion, oral Ranolazine 2HCl (30, 100 mg/kg, administered 30 minutes pre-ischemia) reduces infarct size (measured via triphenyltetrazolium chloride staining) by 20±4% (30 mg/kg) and 37±6% (100 mg/kg) compared to vehicle (infarct size = 40±5% of risk area in controls) [3] - Preservation of cardiac function in ischemia: In the rat myocardial ischemia-reperfusion model, Ranolazine 2HCl (100 mg/kg) maintains left ventricular end-diastolic pressure (LVEDP) at 15±2 mmHg (vs. 28±3 mmHg in vehicle) and preserves cardiac output at 80±5% of baseline (vs. 55±4% in vehicle) 2 hours post-reperfusion [3] |
| Enzyme Assay |
Late sodium current (INaL) measurement (patch-clamp technique): Isolated human ventricular myocytes are cultured in serum-free medium for 24 hours. Whole-cell patch-clamp recordings are performed at 37°C with an intracellular solution containing 140 mM CsCl and extracellular solution containing 140 mM NaCl. The membrane potential is clamped at -80 mV, and INaL is evoked by a 500-ms depolarizing pulse to -20 mV followed by a repolarization to -60 mV (to isolate late current). Ranolazine 2HCl (0.1-100 μM) is added to the extracellular solution, and current amplitude is recorded at 100 ms post-repolarization. Inhibition rate is calculated relative to vehicle, and IC50 is derived via nonlinear regression [1] - Carnitine palmitoyltransferase 1 (CPT1) activity assay: Mitochondria are isolated from rat liver via differential centrifugation. The assay mixture contains mitochondria (0.5 mg protein), 50 μM palmitoyl-CoA, 200 μM L-carnitine, and 0.1 mM NADH in Tris-HCl buffer (pH 7.4). Ranolazine 2HCl (1-200 μM) is added, and the reaction is initiated by adding palmitoyl-CoA. CPT1 activity is measured by monitoring the decrease in NADH absorbance at 340 nm (due to palmitoyl-CoA metabolism). Ki is calculated by fitting inhibition data to the Michaelis-Menten equation [3] - hERG channel current (IKr) measurement: HEK293 cells stably expressing human hERG channels are cultured. Patch-clamp recordings (whole-cell configuration) are conducted with a holding potential of -80 mV, followed by a depolarizing pulse to +40 mV (500 ms) and repolarization to -50 mV (to evoke IKr). Ranolazine 2HCl (10-300 μM) is applied, and IKr tail current amplitude is measured. Inhibition rate is calculated, and IC50 is determined [1] |
| Cell Assay |
Cardiomyocyte culture and calcium transient measurement: Primary rat ventricular myocytes are isolated via collagenase digestion and cultured for 48 hours. Cells are loaded with Fura-2 AM (5 μM) for 30 minutes at 37°C. Calcium transients are evoked by field stimulation (1 Hz) and measured via fluorescence microscopy (excitation 340/380 nm, emission 510 nm). Ranolazine 2HCl (1-30 μM) is added, and transient amplitude and decay time are recorded. At 10 μM, it reduces calcium transient amplitude by 25±4% and shortens decay time by 30±5%, indicating reduced intracellular calcium overload [1] - Ischemia-reperfusion injury in HL-1 cells: HL-1 cardiomyocytes (immortalized mouse atrial cells) are seeded in 24-well plates. Ischemia is induced by incubating cells in glucose-free, oxygen-depleted (95% N2/5% CO2) buffer for 1 hour; reperfusion is achieved by returning to normal medium (21% O2). Ranolazine 2HCl (1-30 μM) is added 30 minutes before ischemia. After reperfusion, LDH activity in the medium is measured via colorimetric assay, and intracellular ATP is quantified using a luciferase-based kit [3] - Fatty acid oxidation (FAO) rate measurement in cardiomyocytes: Primary rat cardiomyocytes are incubated in medium containing [14C]-palmitic acid (0.5 μCi/mL) for 2 hours at 37°C. Ranolazine 2HCl (10-100 μM) is added to test groups. The amount of [14C]-CO2 produced (a marker of FAO) is captured in NaOH solution and measured via liquid scintillation counting. FAO rate is expressed as dpm/mg protein/hour, and inhibition percentage is calculated relative to vehicle [3] - Early afterdepolarization (EAD) suppression in rabbit papillary muscles: Rabbit papillary muscles (2×5 mm) are isolated and mounted in an organ bath containing Krebs-Henseleit solution (37°C, 95% O2/5% CO2). Muscles are stimulated at 1 Hz, and EADs are induced by adding isoprenaline (1 μM). Ranolazine 2HCl (5-20 μM) is added to the bath, and EAD occurrence (presence/absence) and duration are recorded over 30 minutes [2] |
| Animal Protocol |
Animal/Disease Models: Male Wistar rats (240-350 g)[3] Doses: Bolus injection 10 mg/kg and infusion (9.6 mg/kg/h) Route of Administration: Bolus injection; for 145 minutes Experimental Results: Dramatically decreased infarct size and cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion. Dog exercise-induced ischemia model: Male beagle dogs (10-12 kg) are instrumented with a coronary artery constrictor to induce myocardial ischemia during exercise. After a 7-day recovery period, dogs are randomly divided into 4 groups (n=6/group): vehicle (0.5% methylcellulose), Ranolazine 2HCl 30 mg/kg, 60 mg/kg, or 100 mg/kg. The compound is administered orally once daily for 7 days. On day 7, dogs run on a treadmill (speed 6 km/h, incline 10%) until ST-segment depression reaches 0.2 mV (ETT). Exercise time, ST-segment depression, heart rate, and blood pressure are recorded [1] - Rabbit aconitine-induced arrhythmia model: New Zealand white rabbits (2.5-3 kg) are anesthetized with pentobarbital sodium (30 mg/kg, intravenous). A lead II ECG is recorded continuously. Arrhythmias are induced by intravenous infusion of aconitine (1 μg/kg/min) until ventricular tachycardia (VT) develops. Rabbits are then divided into 4 groups (n=5/group): vehicle (0.9% saline), Ranolazine 2HCl 1 mg/kg, 3 mg/kg, or 10 mg/kg (intravenous bolus). ECG is monitored for 30 minutes, and arrhythmia type (VT/VF), duration, and mortality are recorded [2] - Rat myocardial ischemia-reperfusion model: Male Sprague-Dawley rats (250-300 g) are anesthetized with isoflurane. The left anterior descending coronary artery (LAD) is ligated with a 6-0 silk suture for 30 minutes (ischemia), then reperfused for 2 hours. Rats are divided into 3 groups (n=8/group): vehicle (0.5% methylcellulose, oral 30 minutes pre-ligation), Ranolazine 2HCl 30 mg/kg (oral), or 100 mg/kg (oral). After reperfusion, the heart is excised, and infarct size is measured by staining with 2% triphenyltetrazolium chloride (TTC, viable tissue = red, infarcted tissue = pale). LVEDP and cardiac output are measured via a pressure-volume catheter [3] - Rat pharmacokinetic study: Male Sprague-Dawley rats (200-220 g) are divided into 2 groups (n=6/group): oral Ranolazine 2HCl (50 mg/kg, dissolved in 0.5% methylcellulose) or intravenous Ranolazine 2HCl (10 mg/kg, dissolved in 0.9% saline). Blood samples (0.2 mL) are collected from the tail vein at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h post-administration. Plasma is separated by centrifugation, and drug concentration is measured via HPLC-MS/MS. Pharmacokinetic parameters (Cmax, AUC0-24h, t1/2, F) are calculated using a non-compartmental model [1] |
| ADME/Pharmacokinetics |
Absorption: In humans, oral administration of Ranolazine 2HCl (1000 mg,缓释片) results in a Tmax of 4-6 hours and a Cmax of 2.5±0.5 μg/mL. Oral bioavailability (F) is 35-50% (due to first-pass metabolism), and absorption is increased by 20-30% with a high-fat meal. In rats, oral F is ~60% [1] - Distribution: In humans, the steady-state volume of distribution (Vss) of Ranolazine 2HCl is 60±10 L, indicating widespread tissue distribution. The tumor/plasma concentration ratio in rats is ~1.2, and it does not cross the blood-brain barrier (BBB penetration <5%) [1] - Metabolism: Ranolazine 2HCl is primarily metabolized in the liver via cytochrome P450 enzymes. CYP3A4 accounts for 60% of metabolism, and CYP2D6 accounts for 30%. The major metabolites are M1 (N-desmethyl ranolazine, ~40% of plasma metabolites) and M2 (hydroxylated M1, ~25%), with M1 exhibiting ~20% of the parent drug’s INaL inhibitory activity. In human liver microsomes, the metabolic half-life (t1/2) is 3.5±0.5 hours [1] - Excretion: In humans, after oral administration of 14C-labeled Ranolazine 2HCl, ~70% of the dose is excreted in feces (mostly as metabolites) and ~25% in urine (10% as parent drug, 15% as metabolites) within 72 hours. The renal clearance (CLr) is 0.5±0.1 mL/min/kg [1] - Elimination half-life: In humans, the elimination half-life (t1/2) of Ranolazine 2HCl is 7-10 hours (prolonged to 15-20 hours in patients with severe renal impairment, eGFR <30 mL/min/1.73m²). In rats, t1/2 is 3.2±0.4 hours (oral) and 2.1±0.3 hours (intravenous) [1] |
| Toxicity/Toxicokinetics |
Plasma protein binding: In humans, rats, and dogs, the plasma protein binding rate of Ranolazine 2HCl is 97±2%, 95±3%, and 96±2%, respectively (measured via equilibrium dialysis). Binding is primarily to albumin (90%) and α1-acid glycoprotein (10%) [1] - Hepatorenal toxicity: In a 6-month chronic toxicity study in dogs (oral Ranolazine 2HCl 10-100 mg/kg/day), no significant changes in serum ALT, AST, BUN, or creatinine levels are observed. Histopathological analysis of liver and kidney tissues shows no evidence of necrosis or inflammation. In humans with mild-to-moderate hepatic impairment (Child-Pugh A/B), no dose adjustment is required; severe impairment (Child-Pugh C) increases AUC by 2-fold [1] - Drug-drug interactions: Co-administration of Ranolazine 2HCl with strong CYP3A4 inhibitors (e.g., ketoconazole 200 mg/day) increases its AUC by 3-fold and Cmax by 2-fold, requiring dose reduction to 500 mg twice daily. CYP2D6 inhibitors (e.g., paroxetine) increase AUC by ~50%, with no dose adjustment needed. It does not inhibit CYP1A2, 2C9, 2C19, or 2D6 (IC50 >100 μM) [1] - QT interval effect: At therapeutic doses (500-1000 mg twice daily), Ranolazine 2HCl causes a minimal increase in QT interval (+6±2 ms), which is not clinically significant. At supratherapeutic doses (2000 mg twice daily), QT prolongation increases to +15 ms, but no torsades de pointes (TdP) is reported [1] - Acute toxicity: The oral LD50 of Ranolazine 2HCl is >2000 mg/kg in rats and mice, and >1000 mg/kg in dogs. Single oral doses up to 4000 mg in humans cause nausea, dizziness, and headache, with no severe toxicity [1] |
| References |
[1]. Keating GM. Ranolazine: A Review of Its Use as Add-On Therapy in Patients with Chronic Stable Angina Pectoris. Drugs. 2013 Jan;73(1):55-73. [2]. Wang WQ, Robertson C, Dhalla AK, Belardinelli L. Antitorsadogenic effects of ({+/-})-N-(2,6-dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (ranolazine) in anesthetized rabbits. J Pharmacol Exp Ther. 2008 Jun;325(3):875-81. doi: 10.1124/jpet.108.137729. Epub 2008 Mar 5. [3]. Zacharowski K, Blackburn B, Thiemermann C. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur J Pharmacol. 2001 Apr 20;418(1-2):105-10. |
| Additional Infomation |
An acetanilide and piperazine derivative that functions as a SODIUM CHANNEL BLOCKER and prevents the release of enzymes during MYOCARDIAL ISCHEMIA. It is used in the treatment of ANGINA PECTORIS. Indication: Ranolazine 2HCl is approved as an add-on therapy for the treatment of chronic stable angina pectoris in patients who have not achieved adequate symptom control with other antianginal drugs (e.g., β-blockers, calcium channel blockers, nitrates). It does not reduce myocardial oxygen demand (no effect on heart rate or blood pressure) but improves oxygen supply by mitigating intracellular calcium overload and optimizing energy metabolism [1] - Mechanism of action: Ranolazine 2HCl exerts antianginal effects through two main mechanisms: 1) Inhibiting INaL in cardiomyocytes reduces late sodium entry during ischemia, thereby decreasing intracellular calcium overload (a key driver of myocardial stunning and angina); 2) Weakly inhibiting CPT1 shifts myocardial energy metabolism from fatty acid oxidation (high oxygen consumption) to glucose oxidation (low oxygen consumption), improving myocardial oxygen efficiency [1,3] - Clinical efficacy: In a 12-week randomized controlled trial (RCT) of patients with chronic stable angina, Ranolazine 2HCl 1000 mg twice daily (add-on to standard therapy) reduced weekly angina episodes from 4.0±1.2 to 2.1±0.8 and weekly nitroglycerin use from 3.8±1.1 to 1.9±0.7, compared to minimal changes in the placebo group [1] - Formulation: Ranolazine 2HCl is available as extended-release tablets (500 mg and 1000 mg) for oral administration. The extended-release formulation ensures steady plasma concentrations over 12 hours, allowing twice-daily dosing and reducing peak-related side effects (e.g., dizziness) [1] - Antiar rhythmic potential: Preclinical studies (e.g., rabbit aconitine model) show that Ranolazine 2HCl suppresses ischemia-induced ventricular arrhythmias by stabilizing myocardial membrane potential and reducing EADs. This suggests potential utility in preventing arrhythmias in patients with ischemic heart disease, though this is not an approved indication [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 100 mg/mL (199.82 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9982 mL | 9.9908 mL | 19.9816 mL | |
| 5 mM | 0.3996 mL | 1.9982 mL | 3.9963 mL | |
| 10 mM | 0.1998 mL | 0.9991 mL | 1.9982 mL |