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
History
Dofetilide was synthesized in the late 1980s by Pfizer’s medicinal chemistry group led by Michael R. Laufman as a methanesulfonanilide derivative designed to block the rapid component of the delayed rectifier potassium current (IKr) without ancillary sodium- or beta-receptor activity, and the key composition-of-matter patent (US 4959366) was filed on 28 November 1988 and granted on 25 September 1990, providing the intellectual-property foundation for subsequent clinical development. Between 1993 and 1997 the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study randomised 1 518 patients with severe left-ventricular dysfunction to dofetilide or placebo, showing no excess mortality and a significant 26 % reduction in hospitalisation for worsening heart failure, data that underpinned the New Drug Application submitted to the FDA on 30 June 1998. After a 15-month review that included an advisory-panel recommendation for approval contingent on a risk-management programme, the agency granted marketing authorisation on 1 October 1999 for the acute conversion and chronic maintenance of sinus rhythm in highly symptomatic atrial fibrillation/flutter, launching the product as Tikosyn® through a restricted distribution system requiring physician certification and inpatient initiation because of the dose-dependent risk of torsade de pointes. Post-marketing requirements were fulfilled by the continued-access study that treated >3 000 additional subjects, and the Risk Evaluation and Mitigation Strategy (REMS) was progressively relaxed, finally being rescinded by the FDA in January 2016, thereby allowing unrestricted outpatient prescribing while preserving the core label warnings regarding renal dosing and QT monitoring.
Uses
Dofetilide (90%) , is a potassium channel blocker. Antidysrhythmic drug.
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.
References
[1] M GWILT. UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.[J]. Journal of Pharmacology and Experimental Therapeutics, 1991, 256 1: 318-324.
[2] D J SNYDERS A C. High affinity open channel block by dofetilide of HERG expressed in a human cell line.[J]. Molecular Pharmacology, 1996, 49 6: 949-955.
