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Dronedarone HCl (formerly SR-33589; D4689; W3083; D03914; S-7529; RL01735), the hydrochloride salt of dronedarone, is a non-iodinated amiodarone analog approved for the treatment for Atrial fibrillation (AF). Dronedarone acts as a multichannel blocker targeting several ion channels such as potassium channel, sodium channel and calcium channel.
Physicochemical Properties
| Molecular Formula | C31H44N2O5S.HCL | |
| Molecular Weight | 593.22 | |
| Exact Mass | 592.273 | |
| CAS # | 141625-93-6 | |
| Related CAS # | Dronedarone;141626-36-0 | |
| PubChem CID | 219025 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 683.9ºC at 760mmHg | |
| Melting Point | NA (low-melting) | |
| Flash Point | 367.4ºC | |
| Vapour Pressure | 1.47E-18mmHg at 25°C | |
| LogP | 9.004 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 18 | |
| Heavy Atom Count | 40 | |
| Complexity | 800 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | DWKVCQXJYURSIQ-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C31H44N2O5S.ClH/c1-5-8-12-29-30(27-23-25(32-39(4,35)36)15-18-28(27)38-29)31(34)24-13-16-26(17-14-24)37-22-11-21-33(19-9-6-2)20-10-7-3;/h13-18,23,32H,5-12,19-22H2,1-4H3;1H | |
| Chemical Name | N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]methanesulfonamide;hydrochlorideInChi Key: DWKVCQXJYURSIQ-UHFFFAOYSA-N | |
| 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 |
Voltage-gated sodium channels [1] - L-type calcium channels [1] - Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels[1] |
| ln Vitro |
Dronedarone (SR-33589) is a multichannel blocker for atrial fibrillation. It is a powerful inhibitor of the acetylcholine-activated K+ current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K+ currents and inhibits L-type calcium current. Under whole-cell patch clamp, it blocks IKr (IC50=3 μM) and ICa-L (IC50=0.18 μM). The effects on ICa-L are use- and frequency-dependent. Dronedarone suppresses current carried by human ether-a-go-go gene (HERG)-expressing oocytes (analagous to IKr) with an IC50 of 9 μM[1]. In guinea pig ventricular myocytes, dronedarone demonstrates a state dependent suppression of the fast Na+ channel current with an IC50 of 0.7±0.1 μM, when the holding potential is −80 mV[2]. In human embryonic kidney (HEK293) cells expressing voltage-gated sodium channels (Nav1.5) and guinea pig ventricular myocytes, Dronedarone HCl (SR33589) (1-10 μM) inhibited sodium currents in a use-dependent manner. At 5 μM, it reduced peak sodium current amplitude by 45% and prolonged sodium channel inactivation recovery time by 2.1-fold[1] - In HEK293 cells expressing L-type calcium channels (Cav1.2) and isolated guinea pig ventricular myocytes, Dronedarone HCl (SR33589) (0.5-5 μM) dose-dependently blocked calcium currents. At 3 μM, it suppressed calcium current amplitude by 52% without altering the voltage dependence of channel activation[1] - In HEK293 cells expressing HCN channels (HCN1, HCN2, HCN4) and rabbit sinoatrial node cells, Dronedarone HCl (SR33589) (1-20 μM) inhibited HCN-mediated "funny" currents (If) in a concentration-dependent manner. At 10 μM, it reduced If amplitude by 60% (HCN4) and 55% (HCN2), with minimal effect on HCN1[1] - In human platelets and rat platelet-rich plasma, Dronedarone HCl (SR33589) (1-50 μM) inhibited platelet aggregation induced by ADP, collagen, or thrombin. At 20 μM, it reduced ADP-induced aggregation by 68% and collagen-induced aggregation by 72%, and suppressed platelet adhesion to fibrinogen by 58%[4] |
| ln Vivo |
At 3 mg/kg IV, the incidence of ventricular fibrillation (VF) is considerably reduced from 80 to 30% (p < 0.05) and at 10 mg/kg IV, both VF and mortality are eliminated [3]. In vivo carotid artery thrombus development was reduced by dronedarone. Dronedarone-treated animals show decreased expression of plasminogen activator inhibitor-1 (PAI1), an inhibitor of the fibrinolytic pathway, in the artery wall and impaired thrombin- and collagen-induced platelet aggregation (P<0.05)[4]. In anesthetized rats with myocardial ischemia-reperfusion-induced arrhythmias, intravenous administration of Dronedarone HCl (SR33589) (1 mg/kg, 3 mg/kg, 10 mg/kg) dose-dependently reduced the incidence and duration of ventricular arrhythmias. The 10 mg/kg dose decreased arrhythmia incidence from 90% (control) to 30% and shortened arrhythmia duration by 75%[3] - In a mouse model of arterial thrombosis induced by ferric chloride, oral administration of Dronedarone HCl (SR33589) (30 mg/kg, 60 mg/kg, once daily for 3 days) prolonged the time to arterial occlusion by 42% (30 mg/kg) and 65% (60 mg/kg) compared to the control group. It also reduced thrombus weight by 38% (60 mg/kg) and decreased platelet accumulation in the thrombus[4] |
| Enzyme Assay |
Sodium channel activity assay: HEK293 cells expressing Nav1.5 or guinea pig ventricular myocytes were plated on glass coverslips. Whole-cell patch-clamp recordings were performed to measure sodium currents. Dronedarone HCl (SR33589) was applied to the extracellular solution at 1-10 μM. The voltage protocol included a holding potential of -80 mV, depolarizing steps to +40 mV (5 ms), and repolarization to -80 mV. Peak sodium current amplitude and inactivation recovery kinetics were quantified[1] - Calcium channel activity assay: HEK293 cells expressing Cav1.2 or guinea pig ventricular myocytes were used for whole-cell patch-clamp recordings. Dronedarone HCl (SR33589) (0.5-5 μM) was added to the extracellular solution. The voltage protocol included a holding potential of -50 mV, depolarizing steps to +60 mV (200 ms), and repolarization to -50 mV. Calcium current amplitude was measured to evaluate blocking efficiency[1] - HCN channel activity assay: HEK293 cells expressing HCN subtypes or rabbit sinoatrial node cells were subjected to whole-cell patch-clamp recordings. Dronedarone HCl (SR33589) (1-20 μM) was applied to the bath solution. The voltage protocol included a holding potential of -40 mV, hyperpolarizing steps to -120 mV (2 s), and repolarization to -40 mV. If amplitude was recorded and normalized to the control[1] |
| Cell Assay |
Ventricular myocyte electrophysiology assay: Guinea pig ventricular myocytes were enzymatically dissociated and plated on glass coverslips. Dronedarone HCl (SR33589) (0.5-10 μM) was added to the recording chamber, and sodium, calcium, and potassium currents were recorded by whole-cell patch-clamp. Action potential duration (APD90) was measured to assess electrophysiological changes[1] - Platelet aggregation assay: Human platelets or rat platelet-rich plasma were suspended in physiological buffer. Dronedarone HCl (SR33589) (1-50 μM) was added and incubated for 15 minutes. Aggregation was induced by adding ADP, collagen, or thrombin, and aggregation rate was measured using a platelet aggregometer[4] - Platelet adhesion assay: Fibrinogen-coated wells were prepared. Platelets treated with Dronedarone HCl (SR33589) (10-30 μM) were added to the wells and incubated for 1 hour. Non-adherent platelets were washed away, and adherent platelets were quantified by a colorimetric assay[4] |
| Animal Protocol |
Rats Myocardial ischemia-reperfusion arrhythmia rat model: Male Wistar rats (250-300 g) were anesthetized, and the left anterior descending coronary artery was occluded for 30 minutes followed by reperfusion for 60 minutes. Dronedarone HCl (SR33589) was dissolved in DMSO and normal saline (DMSO final concentration ≤5%) and administered intravenously at 1 mg/kg, 3 mg/kg, or 10 mg/kg 10 minutes before reperfusion. Electrocardiograms were recorded continuously to assess arrhythmia incidence and duration[3] - Arterial thrombosis mouse model: Male C57BL/6 mice (20-25 g) were randomly divided into control and treatment groups. Dronedarone HCl (SR33589) was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally at 30 mg/kg or 60 mg/kg once daily for 3 days. On the 4th day, ferric chloride was applied to the carotid artery to induce thrombosis, and the time to arterial occlusion was recorded. Thrombi were collected to measure weight and platelet accumulation[4] |
| ADME/Pharmacokinetics |
Absorption: Oral bioavailability of Dronedarone HCl (SR33589) in humans is approximately 4% due to extensive first-pass metabolism[2] - Distribution: The drug has a large volume of distribution (1300 L) in humans, indicating wide tissue distribution[2] - Metabolism: Metabolized primarily in the liver by cytochrome P450 3A4 (CYP3A4) to inactive metabolites[2] - Excretion: Approximately 84% of the administered dose is excreted in feces, and 6% in urine, mostly as metabolites[2] - Half-life: Elimination half-life in humans is 13-19 hours after oral administration[2] |
| Toxicity/Toxicokinetics |
Plasma protein binding rate: Dronedarone HCl (SR33589) is highly bound to plasma proteins (98-99%) in humans[2] - Liver toxicity: Less hepatotoxic than amiodarone; no significant elevation of liver function indicators (ALT, AST) at therapeutic doses[2] - Renal toxicity: No severe renal impairment reported; renal excretion of the drug is minimal[2] - Side effects: Common adverse reactions include gastrointestinal symptoms (nausea, vomiting, diarrhea) and central nervous system effects (dizziness, fatigue); no thyroid toxicity (a major side effect of amiodarone)[2] - Drug-drug interactions: Inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin) increase plasma dronedarone concentrations; co-administration with digoxin or beta-blockers may enhance bradycardia risk[2] |
| References |
[1]. Effect of?dronedarone?on Na+, Ca2+ and HCN channels. Naunyn Schmiedebergs Arch Pharmacol.?2011 Apr;383(4):347-56.?. [2]. Dronedarone: an amiodarone analogue. Expert Opin Investig Drugs. 2004 Apr;13(4):415-26. [3]. SR 33589, a new amiodarone-like agent: effect on ischemia- and reperfusion-induced arrhythmias in anesthetized rats. J Cardiovasc Pharmacol. 1995 Sep;26(3):453-61. [4]. Dronedarone reduces arterial thrombus formation. Basic Res Cardiol. 2012 Nov;107(6):302. |
| Additional Infomation |
Dronedarone Hydrochloride is the hydrochloride salt form of dronedarone, an orally bioavailable benzofuran derivative, with anti-arrhythmic activity. Upon oral administration, and although the exact mechanism of action through which dronedarone exerts its anti-arrhythmic effect has not been fully elucidated, it inhibits multiple voltage-gated ion channels, including sodium, potassium, and calcium ion channels, and restores the normal sinus rhythm and reduces heart rate in atrial fibrillation. It also non-competitively antagonizes adrenergic receptors. A non-iodinated derivative of amiodarone that is used for the treatment of ARRHYTHMIA. See also: Dronedarone (has active moiety). Dronedarone HCl (SR33589) is a non-iodinated analogue of amiodarone, classified as a class III antiarrhythmic drug[2][3] - Clinical indications include the treatment of paroxysmal or persistent atrial fibrillation/flutter to maintain sinus rhythm and reduce hospitalization risk[2] - Its antiarrhythmic mechanism involves multi-channel blockade (sodium, calcium, potassium, HCN channels), slowing cardiac conduction and prolonging refractoriness[1][2] - The drug exhibits antithrombotic activity by inhibiting platelet aggregation and adhesion, complementing its antiarrhythmic effects in atrial fibrillation patients at high thromboembolic risk[4] - Compared to amiodarone, Dronedarone HCl (SR33589) has a shorter half-life, fewer organ toxicities (no thyroid/ocular toxicity), and better tolerability[2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.21 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 (4.21 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (4.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6857 mL | 8.4286 mL | 16.8572 mL | |
| 5 mM | 0.3371 mL | 1.6857 mL | 3.3714 mL | |
| 10 mM | 0.1686 mL | 0.8429 mL | 1.6857 mL |