| Candidate ID: | R0627 |
| Source ID: | DB04855 |
| Source Type: | approved |
| Compound Type: |
small molecule
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| Compound Name: |
Dronedarone
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| Synonyms: |
Dronedarone; N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)-methanesulfonamide; N-(2-butyl-3-(p-(3-(dibutylamino)propoxy)benzoyl)-5-benzofuranyl)methanesulfonamide
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| Molecular Formula: |
C31H44N2O5S
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| SMILES: |
CCCCN(CCCC)CCCOC1=CC=C(C=C1)C(=O)C1=C(CCCC)OC2=C1C=C(NS(C)(=O)=O)C=C2
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| Structure: |
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| DrugBank Description: |
Dronedarone is a Class III antiarrhythmic drug that works to restore the normal sinus rhythm in patients with paroxysmal or persistent atrial fibrillation. Atrial fibrillation is a common sustained arrhythmia where the treatment primarily focuses on stroke prevention and symptom management. It is managed by rate control, rhythm control, prevention of thromboembolic events, and treatment of the underlying disease. Similar to , dronedarone is a multichannel blocker that works to control rhythm and rate in atrial fibrillation. It meets criteria of all four Vaughan Williams antiarrhythmic drug classes by blocking sodium, potassium, and calcium ion channels and inhibiting β-adrenergic receptors.
Dronedarone is a related benzofuran compound to amiodarone but its chemical structure lacks iodine moieties which are associated with amiodarone-induced thyroid problems. Additionally, the methyl sulfonyl group in its structure renders dronedarone to be more lipophilic with a shorter half-life than amiodarone. This ultimately leads to reduced tissue accumulation of the drug and decreased risk for organ toxicities, such as thyroid and pulmonary toxicities. Commonly marketed as Multaq®, dronedarone was approved by the FDA in July 2009 and Health Canada in August 2009. A safety concern for the risk of drug-induced hepatocellular injury has been issued following marketing of dronedarone.
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| CAS Number: |
141626-36-0
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| Molecular Weight: |
556.756
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| DrugBank Indication: |
Dronedarone is indicated for the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization.
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| DrugBank Pharmacology: |
Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol.
Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure. In animal studies, the use of dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis. Compared to its related compound , dronedarone has a faster onset and offset of actions with a shorter elimination half-life and low tissue accumulation.
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| DrugBank MoA: |
Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke.
Dronedarone achieves heart rate and rhythm control in atrial fibrillation. _In vitro_, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarone is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarone inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarone ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods.
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| Targets: |
Alpha-1A adrenergic receptor antagonist; Alpha-1B adrenergic receptor antagonist; Alpha-1D adrenergic receptor antagonist; Alpha-2A adrenergic receptor antagonist; Alpha-2B adrenergic receptor antagonist; Alpha-2C adrenergic receptor antagonist; Beta-1 adrenergic receptor antagonist; Potassium voltage-gated channel subfamily H member 2 inhibitor; Voltage-dependent L-type calcium channel subunit alpha-1C inhibitor; Voltage-dependent L-type calcium channel subunit alpha-1D inhibitor; Voltage-dependent L-type calcium channel subunit alpha-1F inhibitor; Voltage-dependent L-type calcium channel subunit alpha-1S inhibitor; Voltage-dependent L-type calcium channel subunit beta-1 inhibitor; Voltage-dependent L-type calcium channel subunit beta-2 inhibitor; Voltage-dependent L-type calcium channel subunit beta-3 inhibitor; Voltage-dependent L-type calcium channel subunit beta-4 inhibitor; Potassium channel subfamily K member 2 inhibitor; Sodium channel protein type 5 subunit alpha inhibitor; G protein-activated inward rectifier potassium channel 1 inhibitor; Potassium voltage-gated channel subfamily KQT member 1 inhibitor; Inward rectifier potassium channel inhibitor; Sodium/calcium exchanger 1 inhibitor; Potassium voltage-gated channel subfamily D member 3 inhibitor; Thyroid hormone receptor alpha inhibitor
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| Inclusion Criteria: |
Therapeutic strategy associated
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