DOFETILIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H27N3O5S2
Molecular Weight	441.565
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(CCOC1=CC=C(NS(C)(=O)=O)C=C1)CCC2=CC=C(NS(C)(=O)=O)C=C2

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

Molecular Formula	C19H27N3O5S2
Molecular Weight	441.565
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.drugbank.ca/drugs/DB00204
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

Approval Year

Targets

Primary Target	Pharmacology	Potency
HERG 99 Target ID: CHEMBL240 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12190308	Inhibitor 8504	15.0 nM [IC50]
Potassium channel subfamily K member 2 6 Target ID: CHEMBL2321615 Sources: http://www.drugbank.ca/drugs/DB00204	Inhibitor 8504
ATP-sensitive inward rectifier potassium channel 12 1 Target ID: Q14500 Gene ID: 3768.0 Gene Symbol: KCNJ12 Target Organism: Homo sapiens (Human) Sources: http://www.drugbank.ca/drugs/DB00204	Inhibitor 8504

Conditions

Condition	Modality	Targets	Highest Phase	Product
Atrial fibrillation 131 Sources: https://www.drugs.com/pro/dofetilide.html	Primary		Approved 8583	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 1999

C_max

Value	Dose	Co-administered	Analyte	Population
2054 pg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28800211	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
1807 pg/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28800211	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

AUC

Value	Dose	Co-administered	Analyte	Population
24568 pg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28800211	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
23383 pg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28800211	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
9.54 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28800211	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
9.58 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28800211	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

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4681	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4681
ChemicalBook	CB3381832	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3381832
eMolecules	901787	https://www.emolecules.com/cgi-bin/more?vid=901787
MolPort	MolPort-003-847-012	https://www.molport.com/shop/molecule-link/MolPort-003-847-012
Selleck Chemicals	Dofetilide(Tikosyn)	http://www.selleckchem.com/products/Dofetilide(Tikosyn).html
ZINC	ZINC000000596731	http://zinc15.docking.org/substances/ZINC000000596731

PubMed

Title	Date	PubMed
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.	2003-02	12590905
Dofetilide and atrial fibrillation.	2003-02	12582342
Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels.	2003-02	12566105
Gateways to clinical trials.	2002-12	12616965
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.	2002-11	12382079
Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits.	2002-10-15	12379585
Combined endpoints: can we use them?	2002-10-15	12325112
Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations.	2002-10-04	12354568
Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve.	2002-10	12237256
Pfizer allows community pharmacies to dispense dofetilide.	2002-09-15	12298106
QT interval dynamics predict mortality in high-risk patients after myocardial infarction.	2002-09	12470394
Maintaining stability of sinus rhythm in atrial fibrillation: antiarrhythmic drugs versus ablation.	2002-09	12169239
[Synthesis and vasorelaxant activities of benzopyran-4-one hydrazone derivatives].	2002-08	12567776
How to enhance acute outcome of electrical cardioversion by drug therapy: importance of immediate reinitiation of atrial fibrillation.	2002-08	12212706
The functional properties of the human ether-à-go-go-like (HELK2) K+ channel.	2002-08	12193184
Practitioner acceptance of the dofetilide risk-management program.	2002-08	12173789
New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: design, synthesis, biological assay, and 3D-QSAR analysis.	2002-07-04	12086482
Significance and control of cardiac arrhythmias in patients with congestive cardiac failure.	2002-07	12215733
Prevention of and medical therapy for atrial arrhythmias in heart failure.	2002-07	12215732
Transient atrial mechanical dysfunction (stunning) after cardioversion of atrial fibrillation and flutter.	2002-07	12094183
[Atrial fibrillation in heart failure].	2002-06	12187868
A randomised cross-over study on the haemodynamic effects of oral dofetilide compared with oral sotalol in patients with ischaemic heart disease and sustained ventricular tachycardia.	2002-06	12107600
Protein kinase A-mediated phosphorylation of HERG potassium channels in a human cell line.	2002-05	12133532
Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats.	2002-05	12005366
Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.	2002-04-02	11891067
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?	2002-04-01	11927665
Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery patterns.	2002-03-05	11877367
Effect of dofetilide on QT dispersion and the prognostic implications of changes in QT dispersion for patients with congestive heart failure.	2002-03	11959050
Antidysrhythmic agents at the turn of the twenty-first century: a current review.	2002-03	11939645
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.	2002-03	11862126
Sex, hormones, and repolarization.	2002-02-15	11861044
New antiarrhythmic drugs for the treatment of atrial fibrillation.	2002-02	11916001
Dofetilide block involves interactions with open and inactivated states of HERG channels.	2002-02	11907818
Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K+ channel.	2002-01	11998973
Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval.	2002-01	11849196
A benefit-risk assessment of class III antiarrhythmic agents.	2002	12241126
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.	2001-12	11913480
Dofetilide: what role in the treatment of ventricular tachyarrhythmias?	2001-12	11913474
Effects of the class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes.	2001-12	11804397
A review of class III antiarrhythmic agents for atrial fibrillation: maintenance of normal sinus rhythm.	2001-12	11765303
Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels.	2001-12	11723241
Practical approach to the use and monitoring of dofetilide therapy.	2001-11-01	11715827
Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic.	2001-11	11697758
Drug block of I(kr): model systems and relevance to human arrhythmias.	2001-11	11602820
[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen.	2001-10-26	11698075
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.	2001-10	11907635
Development and evaluation of high throughput functional assay methods for HERG potassium channel.	2001-10	11689132
Management of arrhythmias in heart failure.	2001-04-09	11790264
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.	2001-03	12122969
Frequency dependent prolongation of effective refractory period by a complex class III antiarrhythmic agent CPU-86017.	2001-01	11730558

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

Dofetilide (0.3 microM) inhibited human HERG tail current by 34% +/- 3% and 1% +/- 2% at extracellular pH 7.4 and 6.2, respectively

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:01:16 GMT 2025` Edited by `admin` on `Mon Mar 31 18:01:16 GMT 2025`
Record UNII	R4Z9X1N2ND
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TIKOSYN

Preferred Name

English

DOFETILIDE

Official Name

English

UK-68798

Code

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

Dofetilide [WHO-DD]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175426