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

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 in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group.	1999 Sep 16	10486417
Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation.	2000 May 26	10828461
Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy.	2001 Apr	11509917
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	11913480
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
Pharmacologic management of atrial fibrillation: current therapeutic strategies.	2001 Feb	11174354
Frequency dependent prolongation of effective refractory period by a complex class III antiarrhythmic agent CPU-86017.	2001 Jan	11730558
pH-mediated field-amplified sample stacking of pharmaceutical cations in high-ionic strength samples.	2001 Jan	11197180
Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo.	2001 Jul	11431663
What niche will newer class III antiarrhythmic drugs occupy?	2001 Jul	11406090
Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy.	2001 Jul 17	11457747
Class III antiarrhythmics and phenytoin: teratogenicity due to embryonic cardiac dysrhythmia and reoxygenation damage.	2001 Jun	11375779
"Use-dependent" effects of cisapride on postrest action potentials in rabbit ventricular myocardium.	2001 Jun 22	11430924
Potential ionic mechanism for repolarization differences between canine right and left atrium.	2001 Jun 8	11397783
How to manage atrial fibrillation: an update on recent clinical trials.	2001 Mar-Apr	11209144
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
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	11907635
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
Pericardioversion dofetilide does not suppress immediate and subacute recurrences of persistent atrial fibrillation.	2001 Sep 11	11551891
Dofetilide: a new class III antiarrhythmic for the management of atrial fibrillation.	2001 Summer	11464435
Evaluation of Pulsincap to provide regional delivery of dofetilide to the human GI tract.	2002 Apr 2	11891067
[Synthesis and vasorelaxant activities of benzopyran-4-one hydrazone derivatives].	2002 Aug	12567776
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
Gateways to clinical trials.	2002 Dec	12616965
Dofetilide block involves interactions with open and inactivated states of HERG channels.	2002 Feb	11907818
Sex, hormones, and repolarization.	2002 Feb 15	11861044
Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval.	2002 Jan	11849196
Management of arrhythmias in heart failure.	2002 Jan-Feb	11790264
Significance and control of cardiac arrhythmias in patients with congestive cardiac failure.	2002 Jul	12215733
[Atrial fibrillation in heart failure].	2002 Jun	12187868
Antidysrhythmic agents at the turn of the twenty-first century: a current review.	2002 Mar	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 Mar	11862126
Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery patterns.	2002 Mar 5	11877367
Protein kinase A-mediated phosphorylation of HERG potassium channels in a human cell line.	2002 May	12133532
QT interval dynamics predict mortality in high-risk patients after myocardial infarction.	2002 Sep	12470394
Maintaining stability of sinus rhythm in atrial fibrillation: antiarrhythmic drugs versus ablation.	2002 Sep	12169239
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	12590905
Dofetilide and atrial fibrillation.	2003 Feb	12582342

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

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