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 92 Target ID: CHEMBL240 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12190308	Inhibitor 8297	15.0 nM [IC50]
Potassium channel subfamily K member 2 6 Target ID: CHEMBL2321615 Sources: http://www.drugbank.ca/drugs/DB00204	Inhibitor 8297
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 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Atrial fibrillation 131 Sources: https://www.drugs.com/pro/dofetilide.html	Primary		Approved 8429	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
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
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

AUC

Value	Dose	Co-administered	Analyte	Population
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
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

T_1/2

Value	Dose	Co-administered	Analyte	Population
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
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

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
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
eMolecules	901787	https://www.emolecules.com/cgi-bin/more?vid=901787

PubMed

Title	Date	PubMed
Dofetilide, a new class III antiarrhythmic agent.	2000 Jul	10907968
Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation.	2000 May 26	10828461
Dofetilide (Tikosyn): a new drug to control atrial fibrillation.	2001 Apr	11326815
The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF.	2001 Apr	11282080
Dofetilide: what role in the treatment of ventricular tachyarrhythmias?	2001 Dec	11913474
Effects of the class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes.	2001 Dec	11804397
A review of class III antiarrhythmic agents for atrial fibrillation: maintenance of normal sinus rhythm.	2001 Dec	11765303
Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels.	2001 Dec	11723241
[3H]dofetilide binding in SHSY5Y and HEK293 cells expressing a HERG-like K+ channel?	2001 Feb 2	11166283
Frequency dependent prolongation of effective refractory period by a complex class III antiarrhythmic agent CPU-86017.	2001 Jan	11730558
New antiarrhythmic agents for atrial fibrillation.	2001 Jan	11527018
Effects of EGIS-7229 (S 21407), a novel class III antiarrhythmic drug, on myocardial refractoriness to electrical stimulation in vivo and in vitro.	2001 Jan	11152377
Effect of dofetilide on the pharmacokinetics of digoxin.	2001 Jan 15	11152855
Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias.	2001 Jan 19	11166738
Three things you should know when considering the atria: location, location, location.	2001 Jun 8	11397772
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	12122969
Qtc interval as a guide to select those patients with congestive heart failure and reduced left ventricular systolic function who will benefit from antiarrhythmic treatment with dofetilide.	2001 Mar 13	11245647
Dofetilide: is the treatment worse than the disease?	2001 Mar 15	11263616
Left ventricular hypertrophy decreases slowly but not rapidly activating delayed rectifier potassium currents of epicardial and endocardial myocytes in rabbits.	2001 Mar 20	11257089
Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmacological profile.	2001 May	11334836
Impact of sex and gonadal steroids on prolongation of ventricular repolarization and arrhythmias induced by I(K)-blocking drugs.	2001 May 1	11331264
Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic.	2001 Nov	11697758
Drug block of I(kr): model systems and relevance to human arrhythmias.	2001 Nov	11602820
Practical approach to the use and monitoring of dofetilide therapy.	2001 Nov 1	11715827
Development and evaluation of high throughput functional assay methods for HERG potassium channel.	2001 Oct	11689132
[3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen.	2001 Oct 26	11698075
How to enhance acute outcome of electrical cardioversion by drug therapy: importance of immediate reinitiation of atrial fibrillation.	2002 Aug	12212706
The functional properties of the human ether-à-go-go-like (HELK2) K+ channel.	2002 Aug	12193184
Practitioner acceptance of the dofetilide risk-management program.	2002 Aug	12173789
New antiarrhythmic drugs for the treatment of atrial fibrillation.	2002 Feb	11916001
Sex, hormones, and repolarization.	2002 Feb 15	11861044
Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K+ channel.	2002 Jan	11998973
Management of arrhythmias in heart failure.	2002 Jan-Feb	11790264
[Atrial fibrillation in heart failure].	2002 Jun	12187868
Effect of dofetilide on QT dispersion and the prognostic implications of changes in QT dispersion for patients with congestive heart failure.	2002 Mar	11959050
Antidysrhythmic agents at the turn of the twenty-first century: a current review.	2002 Mar	11939645
Effects of dofetilide on cardiovascular tissues from normo- and hypertensive rats.	2002 May	12005366
Combined endpoints: can we use them?	2002 Oct 15	12325112

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 `Fri Dec 15 15:33:46 GMT 2023` Edited by `admin` on `Fri Dec 15 15:33:46 GMT 2023`
Record UNII	R4Z9X1N2ND
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

DOFETILIDE

Official Name

English

UK-68798

Code

English

TIKOSYN

Brand 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

Dofetilide [WHO-DD]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175426