115256-11-6 Usage
Uses
Used in Cardiology:
Dofetilide is used as a potassium channel blocker for the treatment of cardiac patients with highly symptomatic atrial fibrillation. It selectively inhibits the rapidly acting component of the delayed rectifier potassium current (Ikr), prolonging the effective refractory period (ERP) in both atrial and ventricular myocardium and the monophasic action potential duration. This makes it a potent and highly selective class III antiarrhythmic agent without cardiodepressive effects.
Used in Pharmaceutical Industry:
Dofetilide is used as an antidysrhythmic drug in the pharmaceutical industry. It is a novel class III antiarrhythmic agent that has been found to increase atrial and ventricular refractory periods without affecting conduction or sinus node function. This unique property of targeting only one cardiac ion channel makes it an important drug in the treatment of various cardiac arrhythmias.
Originator
Pfizer (US)
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.
Therapeutic Function
Antiarrhythmic
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) Gwilt et al. (1991) UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells; J. Pharmacol. Exp. Ther., 256 318
2) Snyders and Chaudhary, (1996) High affinity open channel block by dofetilide of HERG expressed in a human cell line; Mol. Pharmacol., 49 949
Check Digit Verification of cas no
The CAS Registry Mumber 115256-11-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,5,2,5 and 6 respectively; the second part has 2 digits, 1 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 115256-11:
(8*1)+(7*1)+(6*5)+(5*2)+(4*5)+(3*6)+(2*1)+(1*1)=96
96 % 10 = 6
So 115256-11-6 is a valid CAS Registry Number.
InChI:InChI=1/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3
115256-11-6Relevant articles and documents
METHOD FOR PREPARING N-[4-(2-{[2-(4-METHANE SULFONAMIDOPHENOXY) ETHYL](METHYL)AMINO}ETHYL)PHENYL]METHANESULFONAMIDE (DOFETILIDE)
-
Paragraph 0023, (2019/06/17)
A method for preparing 1-(4-methanesulfonamidophenoxy)-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane (Dofetilide) of formula I by sulfonylation of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane of formula II with N-methylsulfonyl-N′-methylimidazolium chloride of formula III.
Mild Pd-catalyzed N -arylation of methanesulfonamide and related nucleophiles: Avoiding potentially genotoxic reagents and byproducts
Rosen, Brandon R.,Ruble, J. Craig,Beauchamp, Thomas J.,Navarro, Antonio
supporting information; experimental part, p. 2564 - 2567 (2011/06/25)
A convenient, general, and high yielding Pd-catalyzed cross-coupling of methanesulfonamide with aryl bromides and chlorides is reported. The use of this method eliminates concern over genotoxic impurities that can arise when an aniline is reacted with methanesulfonyl chloride. The application of this method to the synthesis of dofetilide is also reported.
Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues
Liu, Hong,Ji, Min,Jiang, Hualiang,Liu, Ligang,Hua, Weiyi,Chen, Kaixian,Ji, Ruyun
, p. 2153 - 2157 (2007/10/03)
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. The 3D-QSAR models proved a good predictive ability, and could describe the steric, electrostatic and hydrophobic requirements for recognition forces of the receptor site. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VI(a-i)). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in μM of compound VI(c) is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable. (C) 2000 Elsevier Science Ltd.
Dofetilide polymorphs
-
, (2008/06/13)
PCT No. PCT/EP98/06641 Sec. 371 Date Nov. 16, 1999 Sec. 102(e) Date Nov. 16, 1999 PCT Filed Oct. 9, 1998 PCT Pub. No. WO99/21829 PCT Pub. Date May 6, 1999The invention relates to the substantially pure dofetilide polymorphs P162, P162a and P143, and to processes for the preparation of, compositions containing and to the uses of, such polymorphs.
Selective class III antiarrhythmic agents. 1. Bis(arylalkyl)amines
Cross,Arrowsmith,Thomas,Gwilt,Burges,Higgins
, p. 1151 - 1155 (2007/10/02)
A series of bis(arylalkyl)amines is described and their effects on prolonging effective refractory period in isolated cardiac tissue listed. Most compounds prolonged the cardiac action potential without significantly altering the maximum rate of depolarization and may be defined as selective class III antiarrhythmic agents. It was found that a particularly advantageous structural feature was to have a methanesulfonamido moiety on both of the aryl rings. Thus, compound 16 [1-(4-methanesulfonamidophenoxy)-2-[N-(4-methanesulfonamidophenethyl)- N-methylamine]ethane] was selected for further investigations. The compound is highly potent and selective class III agent which acts by blockade of cardiac potassium channels.
Anti-arrhythmic agents
-
, (2008/06/13)
A series of [N-alkyl-N-(nitro-, alkylsulphonamido, or amino-phenalkyl)amino]-alkyl, alkoxy or alkylthio phenyl derivatives having utility as anti-arrhythmic agents.
