Identification

Name
Dofetilide
Accession Number
DB00204  (APRD00367)
Type
Small Molecule
Groups
Approved, Investigational
Description

Dofetilide is a class III antiarrhythmic agent that is approved by the Food and Drug Administration (FDA) for the maintenance of sinus rhythm in individuals prone to the formation of atrial fibrillation and flutter, and for the chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.

Structure
Thumb
Synonyms
  • beta-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide
  • Dofetilida
  • Dofetilidum
External IDs
UK-68,798 / UK-68798
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DofetilideCapsule0.125 mg/1OralGreenstone, Llc2016-05-01Not applicableUs
DofetilideCapsule0.5 mg/1OralGreenstone, Llc2016-05-01Not applicableUs
DofetilideCapsule0.25 mg/1OralGreenstone, Llc2016-05-01Not applicableUs
TikosynCapsule0.125 mg/1OralPfizer Laboratories Div Pfizer Inc.1999-10-01Not applicableUs
TikosynCapsule0.25 mg/1OralAvera McKennan Hospital2016-07-29Not applicableUs
TikosynCapsule0.5 mg/1OralPfizer Laboratories Div Pfizer Inc.1999-10-01Not applicableUs
TikosynCapsule0.125 mg/1OralAvera McKennan Hospital2016-06-28Not applicableUs
TikosynCapsule0.25 mg/1OralPfizer Laboratories Div Pfizer Inc.1999-10-01Not applicableUs00069 5810 60 nlmimage10 213e90f4
TikosynCapsule0.5 mg/1OralAvera McKennan Hospital2016-03-28Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DofetilideCapsule0.125 mg/1OralBionpharma Inc.2018-04-11Not applicableUs
DofetilideCapsule0.25 mg/1OralSun Pharma Global FZE2018-10-11Not applicableUs
DofetilideCapsule250 ug/1OralAv Kare, Inc.2018-08-06Not applicableUs
DofetilideCapsule0.125 mg/1OralMayne Pharma2016-06-07Not applicableUs
DofetilideCapsule0.5 mg/1OralNorth Star Rx Llc2018-06-18Not applicableUs
DofetilideCapsule500 ug/1OralSigma Pharm Laboratories, Llc2018-06-11Not applicableUs
DofetilideCapsule0.5 mg/1OralBionpharma Inc.2018-04-11Not applicableUs
DofetilideCapsule0.5 mg/1OralMayne Pharma2016-06-07Not applicableUs
DofetilideCapsule0.125 mg/1OralSun Pharma Global FZE2018-10-11Not applicableUs47335 06120181011 13961 7j6rah
DofetilideCapsule0.25 mg/1OralNorth Star Rx Llc2018-06-18Not applicableUs
Categories
UNII
R4Z9X1N2ND
CAS number
115256-11-6
Weight
Average: 441.565
Monoisotopic: 441.139212369
Chemical Formula
C19H27N3O5S2
InChI Key
IXTMWRCNAAVVAI-UHFFFAOYSA-N
InChI
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
IUPAC Name
N-[4-(2-{[2-(4-methanesulfonamidophenyl)ethyl](methyl)amino}ethoxy)phenyl]methanesulfonamide
SMILES
CN(CCOC1=CC=C(NS(C)(=O)=O)C=C1)CCC1=CC=C(NS(C)(=O)=O)C=C1

Pharmacology

Indication

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

Associated Conditions
Pharmacodynamics

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.

Mechanism of action

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).

TargetActionsOrganism
APotassium voltage-gated channel subfamily H member 2
inhibitor
Human
APotassium channel subfamily K member 2
inhibitor
Human
AATP-sensitive inward rectifier potassium channel 12
inhibitor
Human
Absorption

>90%

Volume of distribution
  • 3 L/kg
Protein binding

60% -70%

Metabolism

Hepatic

Route of elimination
Not Available
Half life

10 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Dofetilide can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Dofetilide can be decreased when combined with (S)-Warfarin.
16-BromoepiandrosteroneThe metabolism of Dofetilide can be decreased when combined with 16-Bromoepiandrosterone.
3,5-diiodothyropropionic acidThe metabolism of Dofetilide can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dofetilide.
5-androstenedioneThe metabolism of Dofetilide can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Dofetilide can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Dofetilide can be decreased when combined with 6-O-benzylguanine.
AbemaciclibThe metabolism of Dofetilide can be decreased when combined with Abemaciclib.
AbexinostatThe risk or severity of QTc prolongation can be increased when Abexinostat is combined with Dofetilide.
Food Interactions
Not Available

References

Synthesis Reference
US4959366
General References
  1. Lenz TL, Hilleman DE: Dofetilide, a new class III antiarrhythmic agent. Pharmacotherapy. 2000 Jul;20(7):776-86. [PubMed:10907968]
  2. Lenz TL, Hilleman DE: Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter. Drugs Today (Barc). 2000 Nov;36(11):759-71. [PubMed:12845335]
  3. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ: Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999 Sep 16;341(12):857-65. [PubMed:10486417]
External Links
Human Metabolome Database
HMDB0014349
KEGG Drug
D00647
KEGG Compound
C07751
PubChem Compound
71329
PubChem Substance
46509127
ChemSpider
64435
BindingDB
50031720
ChEBI
4681
ChEMBL
CHEMBL473
Therapeutic Targets Database
DAP000495
PharmGKB
PA449389
IUPHAR
2604
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dofetilide
ATC Codes
C01BD04 — Dofetilide
FDA label
Download (1.45 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceDrug-induced QT Interval Prolongation / Pharmacodynamics / Pharmacokinetics1
1CompletedOtherDrug-induced QT Interval Prolongation / Pharmacodynamics / Pharmacokinetics1
1CompletedTreatmentDrug-induced Surface ECG Changes1
1CompletedTreatmentLong qt Syndrome1
3SuspendedTreatmentNonvalvular Atrial Fibrillation1
3TerminatedTreatmentHeart Failure, Unspecified / Nonvalvular Atrial Fibrillation1
4WithdrawnTreatmentNonvalvular Atrial Fibrillation1
Not AvailableCompletedTreatmentNonvalvular Atrial Fibrillation1
Not AvailableRecruitingNot AvailableLong qt Syndrome / Therapeutic Agent Toxicity1

Pharmacoeconomics

Manufacturers
  • Pfizer pharmaceuticals production corp ltd
Packagers
  • Pfizer Inc.
Dosage forms
FormRouteStrength
CapsuleOral0.125 mg/1
CapsuleOral0.25 mg/1
CapsuleOral0.5 mg/1
CapsuleOral125 ug/1
CapsuleOral250 ug/1
CapsuleOral500 ug/1
Prices
Unit descriptionCostUnit
Tikosyn 250 mcg capsule3.64USD capsule
Tikosyn 125 mcg capsule3.63USD capsule
Tikosyn 500 mcg capsule3.61USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4959366No1992-09-252012-09-25Us
US6124363No1998-10-092018-10-09Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP2.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0198 mg/mLALOGPS
logP2.17ALOGPS
logP0.24ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)10.15ChemAxon
pKa (Strongest Basic)8.99ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area104.81 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity113.27 m3·mol-1ChemAxon
Polarizability46.03 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9924
Blood Brain Barrier+0.9179
Caco-2 permeable-0.6257
P-glycoprotein substrateSubstrate0.6018
P-glycoprotein inhibitor IInhibitor0.6848
P-glycoprotein inhibitor IINon-inhibitor0.7391
Renal organic cation transporterNon-inhibitor0.7308
CYP450 2C9 substrateNon-substrate0.7572
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.6699
CYP450 1A2 substrateNon-inhibitor0.6359
CYP450 2C9 inhibitorNon-inhibitor0.5189
CYP450 2D6 inhibitorNon-inhibitor0.7709
CYP450 2C19 inhibitorInhibitor0.544
CYP450 3A4 inhibitorNon-inhibitor0.7715
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6823
Ames testNon AMES toxic0.6193
CarcinogenicityNon-carcinogens0.6038
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5430 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8119
hERG inhibition (predictor II)Inhibitor0.8258
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-1610900000-368db21beef81a5319f4
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-0300900000-47394a7ed027cb5ab3cf

Taxonomy

Description
This compound belongs to the class of organic compounds known as sulfanilides. These are organic aromatic compounds containing a sulfanilide moiety, with the general structure RS(=O)(=O)NC1=CC=CC=C1.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Sulfanilides
Direct Parent
Sulfanilides
Alternative Parents
Phenethylamines / Phenoxy compounds / Phenol ethers / Aralkylamines / Alkyl aryl ethers / Organosulfonamides / Organic sulfonamides / Aminosulfonyl compounds / Trialkylamines / Organopnictogen compounds
show 2 more
Substituents
Sulfanilide / Phenethylamine / Phenoxy compound / Phenol ether / Alkyl aryl ether / Aralkylamine / Organic sulfonic acid amide / Organosulfonic acid amide / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary amino compound, aromatic ether, sulfonamide (CHEBI:4681)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Lees-Miller JP, Duan Y, Teng GQ, Duff HJ: Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites. Mol Pharmacol. 2000 Feb;57(2):367-74. [PubMed:10648647]
  2. Overholt JL, Ficker E, Yang T, Shams H, Bright GR, Prabhakar NR: HERG-Like potassium current regulates the resting membrane potential in glomus cells of the rabbit carotid body. J Neurophysiol. 2000 Mar;83(3):1150-7. [PubMed:10712445]
  3. Finlayson K, Pennington AJ, Kelly JS: [3H]dofetilide binding in SHSY5Y and HEK293 cells expressing a HERG-like K+ channel? Eur J Pharmacol. 2001 Feb 2;412(3):203-12. [PubMed:11166283]
  4. Finlayson K, Turnbull L, January CT, Sharkey J, Kelly JS: [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur J Pharmacol. 2001 Oct 26;430(1):147-8. [PubMed:11698075]
  5. Ficker E, Jarolimek W, Brown AM: Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K(+) channels. Mol Pharmacol. 2001 Dec;60(6):1343-8. [PubMed:11723241]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  7. Ficker E, Jarolimek W, Kiehn J, Baumann A, Brown AM: Molecular determinants of dofetilide block of HERG K+ channels. Circ Res. 1998 Feb 23;82(3):386-95. [PubMed:9486667]
  8. Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, Reynolds W, Viviani F, Tabart M, Rampe D: Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol. 2005 Mar;67(3):827-36. Epub 2004 Nov 17. [PubMed:15548764]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Potassium ion leak channel activity
Specific Function
Ion channel that contributes to passive transmembrane potassium transport (PubMed:23169818). Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward...
Gene Name
KCNK2
Uniprot ID
O95069
Uniprot Name
Potassium channel subfamily K member 2
Molecular Weight
47092.215 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Roukoz H, Saliba W: Dofetilide: a new class III antiarrhythmic agent. Expert Rev Cardiovasc Ther. 2007 Jan;5(1):9-19. [PubMed:17187453]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Inward rectifier potassium channel activity
Specific Function
Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable...
Gene Name
KCNJ12
Uniprot ID
Q14500
Uniprot Name
ATP-sensitive inward rectifier potassium channel 12
Molecular Weight
49000.6 Da
References
  1. Kiehn J, Wible B, Lacerda AE, Brown AM: Mapping the block of a cloned human inward rectifier potassium channel by dofetilide. Mol Pharmacol. 1996 Aug;50(2):380-7. [PubMed:8700146]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 12:44