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Details

Stereochemistry ACHIRAL
Molecular Formula C19H27N3O5S2
Molecular Weight 441.5677
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DOFETILIDE

SMILES

CN(CCc1ccc(cc1)NS(=O)(=O)C)CCOc2ccc(cc2)NS(=O)(=O)C

InChI

InChIKey=IXTMWRCNAAVVAI-UHFFFAOYSA-N
InChI=1S/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

HIDE SMILES / InChI

Description
Curator's Comment:: Description was created based on several sources, including https://www.drugs.com/pro/dofetilide.html

Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors. The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway). Used for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm.

Originator

Curator's Comment:: # Pfizer

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
15.0 nM [IC50]
Target ID: Q14500
Gene ID: 3768.0
Gene Symbol: KCNJ12
Target Organism: Homo sapiens (Human)
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Tikosyn

Approved Use

Dofetilide capsules are indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm.

Launch Date

9.3864958E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1807 pg/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DOFETILIDE blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
2054 pg/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DOFETILIDE blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
23383 pg × h/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DOFETILIDE blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
24568 pg × h/mL
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DOFETILIDE blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
9.58 h
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DOFETILIDE blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
9.54 h
0.5 mg single, oral
dose: 0.5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DOFETILIDE blood
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
PubMed

PubMed

TitleDatePubMed
Current management of symptomatic atrial fibrillation.
2001
A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease.
2001 Dec
Dofetilide: what role in the treatment of ventricular tachyarrhythmias?
2001 Dec
A review of class III antiarrhythmic agents for atrial fibrillation: maintenance of normal sinus rhythm.
2001 Dec
Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels.
2001 Dec
Frequency dependent prolongation of effective refractory period by a complex class III antiarrhythmic agent CPU-86017.
2001 Jan
KCB-328 (C&C Research Labs).
2001 Jan
Myocardial repolarization and drugs. Impossibility to predict the dominance of anti-arrhythmic over pro-arrhythmic effects of drugs due to differential and ventricular electrical remodeling.
2001 Mar
Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic.
2001 Nov
Drug block of I(kr): model systems and relevance to human arrhythmias.
2001 Nov
Practical approach to the use and monitoring of dofetilide therapy.
2001 Nov 1
Is it rational, reasonable or excessive, and consistently applied? One view of the increasing FDA emphasis on safety first for the release and use of antiarrhythmic drugs for supraventricular arrhythmias.
2001 Oct
Development and evaluation of high throughput functional assay methods for HERG potassium channel.
2001 Oct
[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen.
2001 Oct 26
Efficacy of azimilide and dofetilide in the dog right atrial enlargement model of atrial flutter.
2001 Sep
Pericardioversion dofetilide does not suppress immediate and subacute recurrences of persistent atrial fibrillation.
2001 Sep 11
Pharmacologic conversion of atrial fibrillation: a systematic review of available evidence.
2001 Sep-Oct
A benefit-risk assessment of class III antiarrhythmic agents.
2002
A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link?
2002 Apr 1
Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.
2002 Apr 2
[Synthesis and vasorelaxant activities of benzopyran-4-one hydrazone derivatives].
2002 Aug
How to enhance acute outcome of electrical cardioversion by drug therapy: importance of immediate reinitiation of atrial fibrillation.
2002 Aug
The functional properties of the human ether-à-go-go-like (HELK2) K+ channel.
2002 Aug
Practitioner acceptance of the dofetilide risk-management program.
2002 Aug
Gateways to clinical trials.
2002 Dec
New antiarrhythmic drugs for the treatment of atrial fibrillation.
2002 Feb
Dofetilide block involves interactions with open and inactivated states of HERG channels.
2002 Feb
Sex, hormones, and repolarization.
2002 Feb 15
Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval.
2002 Jan
Management of arrhythmias in heart failure.
2002 Jan-Feb
Significance and control of cardiac arrhythmias in patients with congestive cardiac failure.
2002 Jul
Prevention of and medical therapy for atrial arrhythmias in heart failure.
2002 Jul
Transient atrial mechanical dysfunction (stunning) after cardioversion of atrial fibrillation and flutter.
2002 Jul
New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: design, synthesis, biological assay, and 3D-QSAR analysis.
2002 Jul 4
[Atrial fibrillation in heart failure].
2002 Jun
Effect of dofetilide on QT dispersion and the prognostic implications of changes in QT dispersion for patients with congestive heart failure.
2002 Mar
Antidysrhythmic agents at the turn of the twenty-first century: a current review.
2002 Mar
Effects of the I(Kr)-blocking agent dofetilide and of the I(Ks)-blocking agent chromanol 293b on regional disparity of left ventricular repolarization in the intact canine heart.
2002 Mar
Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery patterns.
2002 Mar 5
Protein kinase A-mediated phosphorylation of HERG potassium channels in a human cell line.
2002 May
Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide.
2002 Nov
Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve.
2002 Oct
Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits.
2002 Oct 15
Combined endpoints: can we use them?
2002 Oct 15
Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations.
2002 Oct 4
QT interval dynamics predict mortality in high-risk patients after myocardial infarction.
2002 Sep
Maintaining stability of sinus rhythm in atrial fibrillation: antiarrhythmic drugs versus ablation.
2002 Sep
Survival after withdrawal of dofetilide in patients with congestive heart failure and a short baseline QTc interval; a follow-up on the Diamond-CHF QT substudy.
2003 Feb
Dofetilide and atrial fibrillation.
2003 Feb
Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels.
2003 Feb
Patents

Sample Use Guides

Usual Adult Dose for Arrhythmias 125 mcg once a day to 500 mcg twice a day Dose is based on creatinine clearance and QTc interval prolongation. Dose is adjusted 2 to 3 hours after first dose based QTc interval.
Route of Administration: Oral
Dofetilide (0.3 microM) inhibited human HERG tail current by 34% +/- 3% and 1% +/- 2% at extracellular pH 7.4 and 6.2, respectively
Name Type Language
DOFETILIDE
EMA EPAR   INN   JAN   MART.   MI   ORANGE BOOK   USAN   USP   USP-RS   VANDF   WHO-DD  
USAN   INN  
Official Name English
UK-68798
Code English
TIKOSYN
Brand Name English
DOFETILIDE [WHO-DD]
Common Name English
DOFETILIDE [JAN]
Common Name English
DOFETILIDE [EMA EPAR]
Common Name English
DOFETILIDE [USP-RS]
Common Name English
DOFETILIDE [USAN]
Common Name English
DOFETILIDE [VANDF]
Common Name English
DOFETILIDE [MI]
Common Name English
DOFETILIDE [USP MONOGRAPH]
Common Name English
METHANESULFONAMIDE, N-(4-(2-(METHYL(2-(4-((METHYLSULFONYL)AMINO)PHENOXY)ETHYL)AMINO)ETHYL)PHENYL)-
Systematic Name English
.BETA.-((P-METHANESULFONAMIDOPHENETHYL)METHYLAMINO)METHANESULFONO-P-PHENETIDIDE
Common Name English
DOFETILIDE [ORANGE BOOK]
Common Name English
DOFETILIDE [MART.]
Common Name English
UK-68,798
Code English
DOFETILIDE [INN]
Common Name English
Classification Tree Code System Code
NDF-RT N0000175426
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
EMA ASSESSMENT REPORTS TIKOSYN (WITHDRAWN: ATRIAL FIBRILLATION)
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
WHO-ATC C01BD04
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
EMA ASSESSMENT REPORTS TIKOSYN (WIHDRAWN: ATRIAL FLUTTER)
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
NCI_THESAURUS C47793
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
WHO-VATC QC01BD04
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
NCI_THESAURUS C93038
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
Code System Code Type Description
RXCUI
49247
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY RxNorm
INN
6756
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
WIKIPEDIA
DOFETILIDE
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
DRUG CENTRAL
942
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
MERCK INDEX
M4726
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY Merck Index
MESH
C063533
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
FDA UNII
R4Z9X1N2ND
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
PUBCHEM
71329
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
DRUG BANK
DB00204
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
EVMPD
SUB06351MIG
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
CAS
115256-11-6
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
NCI_THESAURUS
C47499
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
EPA CompTox
115256-11-6
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
HSDB
7927
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
USP_CATALOG
1224937
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY USP-RS
IUPHAR
2604
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY
ChEMBL
CHEMBL473
Created by admin on Fri Jun 25 20:54:50 UTC 2021 , Edited by admin on Fri Jun 25 20:54:50 UTC 2021
PRIMARY