115256-11-6

Description

Dofetilide was launched in the US as a novel class III antiarrhythmic for treatment of cardiac patients with highly symptomatic atrial fibrillation This bisarylsulfonamide can be obtained by a three step synthesis starting from 4-nitro-N-methylphenethylamine and involving simultaneous nitro reduction and mesylation on both aromatic amine functions. In contrast to other class III antiarrhythmic agents such as amiodarone, dofetilide potently and selectively inhibits a single potassium channel, Ikr, the rapidly acting component of the delayed rectifier potassium current, Accordingly, by blocking the open state of Ikr, dofetilide is able to prolong the effective refractory period (ERP) in both atrial and ventricular myocardium and the monophasic action potential duration. Moreover, as it targets only one cardiac ion channel, it does not produce any effects on the sinus node, cardiac conduction system and other extracardiac organs, making it unique among established class III agents. Several pharmacological studies with models using different animal species indicated that dofetilide was a potent and highly selective class III antiarrhythmic agent devoid of cardiodepressive effects. During clinical trials in patients with paroxysmal atrial or supraventricular fibrillation, dofetilide was found to increase atrial and ventricular refractory periods without affecting conduction or sinus node function. If increases in the QT/QTc interval after oral or intravenous dofetilide are expected, as for other class III antiarrhythmic agents, other electrocardiographic intervals are unaffected.

Chemical Properties

White Crystalline Solid

Originator

Pfizer (US)

Uses

Potassium channel blocker

Definition

ChEBI: A tertiary amino compound that is N-ethyl-N-methylethanamine substituted by a 4-[(methylsulfonyl)amino]phenoxy and a 4-[(methylsulfonyl)amino]phenyl group at the terminal carbon atoms respectively. It is used as an an i-arrhythmia drug.

Manufacturing Process

To a solution of N-methyl-4-nitrophenethylamine (1.5 g) (J.O.C., [1956], 21, 45) and 2-[4-nitrophenoxy]ethyl chloride (1.55 g) (C.A., [1955], 49, 3163e) in acetonitrile (50 ml) was added potassium carbonate (1.25 g) and sodium iodide (1.2 g) and the suspension was stirred at reflux for 72 hours. After evaporation to dryness, the residual oily solid was partitioned between a 2 N aqueous sodium bicarbonate solution and ethyl acetate. After two further extractions with ethyl acetate, the organic portions were combined, washed with a saturated aqueous brine solution, dried over magnesium sulfate, filtered and evaporated. The resultant orange solid (2.7 g) was crystallised from ethanol to give 1-(4-nitrophenoxy)-2-[N-methyl-N-(4- nitrophenethyl)amino]ethane (1.9 g), m.p. 74°C.A solution of 1-(4-nitrophenoxy)-2-[N-methyl-N-(4- nitrophenethyl)amino]ethane (1.5 g) in ethanol (100 ml) was stirred for 16 hours at room temperature under three atmospheres of hydrogen in the presence of Raney nickel. The reaction mixture was filtered and evaporated to dryness. The residual oil was re-dissolved in ether, filtered and evaporated to give a yellow solid (1.1 g), which was crystallised from ethyl acetate/petroleum ether (b.p. 60-80°C) to give 1-(4-aminophenoxy)-2-[N-(4- aminophenethyl)-N-methylamino]ethane (0.9 g), m.p. 73-74°C.A solution of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-Nmethylamino]ethane (0.75 g) and methanesulphonic anhdyride (1.0 g) in dry methylene chloride (50 ml) was stirred at room temperature overnight. After evaporation, the resultant oil was partitioned between a 2 N aqueous sodium bicarbonate solution and ethyl acetate. After two further extractions with ethyl acetate, the organic portions were combined, dried over magnesium sulfate, filtered and evaporated. The resultant colourless solid (1.2 g) was crystallised from ethyl acetate/methanol to give methanesulfonamide, N-(4-(2-(methyl(2- (4-((methylsulfonyl)amino)phenoxy)ethyl)amino)ethyl)phenyl)-, (0.6 g), m.p. 147-149°C.

Brand name

Tikosyn (Pfizer).

Therapeutic Function

Antiarrhythmic

General Description

Dofetilide, N-[4-(3-{[2-(4-methanesulfonylaminophenyl)ethyl]methylamino}propoxy)phenyl]methane-sulfonamide (Tikosyn), acts by blocking thecardiac ion channel carrying the rapid component of thedelayed rectifier potassium currents (Ikr) and is used toterminate supraventricular arrhythmias, prevent the recurrenceof atrial fibrillation, and treat life-threatening ventriculararrhythmias. Unlike sotalol and ibutilide, whichare also methanesulfonanilides, it has no effect on adrenergicreceptors or sodium channels, respectively. Dofetilidehas high specificity for the delayed rectifier potassiumcurrents.

Biological Activity

Selective potassium channel blocker. Blocks hERG K + channels; inhibits the rapid delayed-rectifier K + current (I Kr ). Displays class III antiarrhythmic properties.

Biochem/physiol Actions

Dofetilide is a Class III antiarrhythmic and hERG channel blocker. Dofetilide selectively blocks the rapid component of the delayed rectifier outward potassium current (IKr).

Clinical Use

Dofetilide (Tikosyn) is a “pure” class III drug. It prolongs the cardiac action potential and the refractory period by selectively inhibiting the rapid component of the delayed rectifier potassium current (IKr). Dofetilide is approved for the treatment of atrial fibrillation and atrial flutter. Because of the lack of significant hemodynamic effects, dofetilide may be useful in patients with CHF who are in need of therapy for supraventricular tachyarrhythmias. Dofetilide is not indicated for use in the setting of ventricular arrhythmias.

Side effects

The incidence of noncardiac adverse events is not different from that of placebo in controlled clinical trials. The principal cardiac adverse effect is the risk of torsades de pointes due to QT prolongation.The risk is approximately 3%, and most cases are observed in the first 3 days of therapy.As such, initiation of therapy should be performed with the patient in hospital.

Drug interactions

Verapamil increases serum dofetilide levels, as do drugs that inhibit cationic renal secretion, such as ketoconazole and cimetidine, raise serum levels.

Metabolism

Dofetlide is used orally to suppress atrial fibrillation and flutter. It is more potent and selective than other Class III methanesulfonanilides, including sotalol. Dofetilide is well absorbed from the gastrointestinal tract, with a bioavailability of 96 to 100%. The bioavailability of oral dofetilide is not affected by food or antacids. Protein binding is 60 to 70%. Dofetilide is metabolized by the hepatic CYP3A4 enzyme system via N-dealkylation and N-oxidation to inactive or minimally active metabolites. Of the approximately 80% of a dose excreted in urine, approximately 80% is excreted unchanged, with the other 20% as metabolites.

Precautions

Contraindications include baseline prolongation of the QT interval, use of other QT-prolonging drugs; history of torsades de pointes; a creatinine clearance of less than 20 mL/minute; simultaneous use of verapamil, cimetidine, or ketoconazole; uncorrected hypokalemia or hypomagnesemia; and pregnancy or breast-feeding.