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Record Information
Version2.0
Creation Date2009-07-05 02:56:03 UTC
Update Date2014-12-24 20:25:41 UTC
Accession NumberT3D2556
Identification
Common NameFlecainide
ClassSmall Molecule
DescriptionA potent anti-arrhythmia agent, effective in a wide range of ventricular and atrial arrhythmias and tachycardias. Paradoxically, however, in myocardial infarct patients with either symptomatic or asymptomatic arrhythmia, flecainide exacerbates the arrhythmia and is not recommended for use in these patients. [PubChem]
Compound Type
  • Amide
  • Amine
  • Anti-Arrhythmia Agent
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
  • Voltage-Gated Sodium Channel Blocker
Chemical Structure
Thumb
Synonyms
Synonym
(+-)-Flecainide
Almarytm
Apocard
CCRIS 313
Flecaine
Flecainida
Flecainidum
N-(2-Piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
Tambocor
Chemical FormulaC17H20F6N2O3
Average Molecular Mass414.343 g/mol
Monoisotopic Mass414.138 g/mol
CAS Registry Number54143-55-4
IUPAC NameN-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
Traditional Nameflecainide
SMILESOC(=NCC1CCCCN1)C1=C(OCC(F)(F)F)C=CC(OCC(F)(F)F)=C1
InChI IdentifierInChI=1/C17H20F6N2O3/c18-16(19,20)9-27-12-4-5-14(28-10-17(21,22)23)13(7-12)15(26)25-8-11-3-1-2-6-24-11/h4-5,7,11,24H,1-3,6,8-10H2,(H,25,26)
InChI KeyInChIKey=DJBNUMBKLMJRSA-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as benzamides. These are organic compounds containing a carboxamido substituent attached to a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassBenzoic acids and derivatives
Direct ParentBenzamides
Alternative Parents
Substituents
  • Benzamide
  • Phenoxy compound
  • Benzoyl
  • Phenol ether
  • Alkyl aryl ether
  • Piperidine
  • Amino acid or derivatives
  • Carboxamide group
  • Secondary carboxylic acid amide
  • Carboxylic acid derivative
  • Secondary aliphatic amine
  • Ether
  • Azacycle
  • Organoheterocyclic compound
  • Secondary amine
  • Organohalogen compound
  • Alkyl halide
  • Alkyl fluoride
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organofluoride
  • Organonitrogen compound
  • Organooxygen compound
  • Amine
  • Organic oxygen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Flecainide PathwayNot AvailableNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceSolid (1).
Experimental Properties
PropertyValue
Melting Point228-229°C
Boiling PointNot Available
Solubility48.4 mg/mL at 37°C (acetate form)
LogP3.78
Predicted Properties
PropertyValueSource
Water Solubility0.032 g/LALOGPS
logP2.98ALOGPS
logP3.19ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)13.68ChemAxon
pKa (Strongest Basic)9.62ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area59.59 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity88.4 m³·mol⁻¹ChemAxon
Polarizability35.92 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0f89-5009000000-7b1564870deda7f2d21eJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00dl-0095000000-644485d209c90776a32dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0190000000-201f2152d161a1ff83e5JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0790000000-928874c4b348381ad1b8JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0596-0940000000-ee7a94ba0d7bcfa2fe93JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-052g-1910000000-a32ac2f605f11fbbc5e0JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0297-1900000000-f1c49d25a6b161ff44d9JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-014i-0000900000-9820e909cb01d45fa815JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00kb-2009500000-68b872fada8afdd4e580JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0f6t-5019000000-8fa5e4257c88beda0ea1JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0uea-8069000000-149a79cf429446ec77c2JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0uei-6292000000-103ccdef98c4b6c9e408JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0pdi-8970000000-9258d139b203d6c98df0JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-014j-5306900000-5bc88ff27c840b41cb32JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0002-9314100000-11d4e9fa034a85ea06f0JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0002-9010000000-ac2b8dd3242c0db13ae9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0004900000-9ea43375c547f2e6b28aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03xu-2139400000-cddcc91db822779e66b6JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00l2-5391000000-60f93403fdd5f22a81c3JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-001i-9000000000-b732167df77d39193144JSpectraViewer | MoNA
Toxicity Profile
Route of ExposureIngestion (MSDS, A308). Nearly complete following oral administration.
Mechanism of ToxicityFlecainide acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers. Flecainide is a sodium channel blocker, binding to voltage gated sodium channels. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole.
MetabolismHepatic. Flecainide does not undergo any consequential presystemic biotransformation. The two major urinary metabolites are meta-O-dealkylated flecainide (active, but about one-fifth as potent) and the meta-O-dealkylated lactam of flecainide (non-active metabolite). The absoprtion is nearly complete following oral administration. Hepatic. Flecainide does not undergo any consequential presystemic biotransformation. The two major urinary metabolites are meta-O-dealkylated flecainide (active, but about one-fifth as potent) and the meta-O-dealkylated lactam of flecainide (non-active metabolite). Route of Elimination: In healthy subjects, about 30% of a single oral dose (range, 10 to 50%) is excreted in urine as unchanged drug. Several minor metabolites (3% of the dose or less) are also found in urine; only 5% of an oral dose is excreted in feces. In patients, free (unconjugated) plasma levels of the two major metabolites are very low (less than 0.05 ug/mL). Half Life: 20 hours (range 12-27 hours)
Toxicity ValuesLD50: 50-498 mg/kg (Oral, Rat) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFlecainide is is a class Ic antiarrhythmic agent and as such, it is used for the prevention of paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disablin (1).
Minimum Risk LevelNot Available
Health EffectsSigns of flecainide toxicity include marked prolongation of the PR interval and widening of the QRS duration on the surface ECG. There may be signs and symptoms attributable to overt heart failure secondary to sudden decreased myocardial contractility (8).
SymptomsSymptoms of overdose include nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest.
TreatmentTreatment of flecainide toxicity involves increasing the excretion of flecainide, blocking its effects in the heart, and (rarely) institution of cardiovascular support to avoid impending lethal arrhythmias. Modalities that have had success include administration of a beta-sympathomimetic agent, and administration of a sodium load (often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily obviate the need for a beating heart and to increase blood flow to the liver. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01195
HMDB IDHMDB15326
PubChem Compound ID3356
ChEMBL IDCHEMBL652
ChemSpider ID3239
KEGG IDC07001
UniProt IDNot Available
OMIM ID
ChEBI ID127588
BioCyc IDNot Available
CTD IDNot Available
Stitch IDFlecainide
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFlecainide
References
Synthesis Reference

Bmitt, E.H. and Brown, W.R.; U.S. Patent 3,900,481; August 19,1975; assigned to Riker Laboratories, Inc.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Gill JS, Mehta D, Ward DE, Camm AJ: Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality. Br Heart J. 1992 Oct;68(4):392-7. [1449923 ]
  3. Sakurada H, Hiyoshi Y, Tejima T, Yanase O, Tokuyasu Y, Watanabe K, Motomiya T, Sugiura M, Hiraoka M: [Effects of oral flecainide treatment of refractory tachyarrhythmias]. Kokyu To Junkan. 1990 May;38(5):471-6. [2115193 ]
  4. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8. [1900101 ]
  5. Greenberg HM, Dwyer EM Jr, Hochman JS, Steinberg JS, Echt DS, Peters RW: Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I. Br Heart J. 1995 Dec;74(6):631-5. [8541168 ]
  6. Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S: Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol. 2003 Jan;26(1 Pt 2):338-41. [12687841 ]
  7. Olson KR (ed) (2007). Poisoning & Drug Overdose. 5th ed. New York, NY: Lange Medical Books/McGraw-Hill.
  8. Wikipedia. Flecainide. Last Updated 8 August 2009. [Link]
  9. Drugs.com [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
Gene Name:
SCN5A
Uniprot ID:
Q14524
Molecular Weight:
226937.475 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC506.5 uMNot AvailableBindingDB 50131434
References
  1. Nagatomo T, January CT, Makielski JC: Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide. Mol Pharmacol. 2000 Jan;57(1):101-7. [10617684 ]
  2. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, Medina A: Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation. 2000 Apr 11;101(14):1698-706. [10758053 ]
  3. Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E: The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000 Aug 29;102(9):945-7. [10961955 ]
  4. Cerrone M, Crotti L, Faggiano G, De Michelis V, Napolitano C, Schwartz PJ, Priori SG: [Long QT syndrome and Brugada syndrome: 2 aspects of the same disease?]. Ital Heart J Suppl. 2001 Mar;2(3):253-7. [11307783 ]
  5. Viswanathan PC, Bezzina CR, George AL Jr, Roden DM, Wilde AA, Balser JR: Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Circulation. 2001 Sep 4;104(10):1200-5. [11535580 ]
  6. Plouvier B, Beatch GN, Jung GL, Zolotoy A, Sheng T, Clohs L, Barrett TD, Fedida D, Wang WQ, Zhu JJ, Liu Y, Abraham S, Lynn L, Dong Y, Wall RA, Walker MJ: Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation. J Med Chem. 2007 Jun 14;50(12):2818-41. Epub 2007 May 17. [17506538 ]
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 delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC503.89 uMNot AvailableBindingDB 50131434
IC503.89045 uMNot AvailableBindingDB 50131434
References
  1. Keseru GM: Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. Bioorg Med Chem Lett. 2003 Aug 18;13(16):2773-5. [12873512 ]
  2. Tobita M, Nishikawa T, Nagashima R: A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors. Bioorg Med Chem Lett. 2005 Jun 2;15(11):2886-90. [15911273 ]
  3. Jia L, Sun H: Support vector machines classification of hERG liabilities based on atom types. Bioorg Med Chem. 2008 Jun 1;16(11):6252-60. doi: 10.1016/j.bmc.2008.04.028. Epub 2008 Apr 16. [18448342 ]
  4. Chiu PJ, Marcoe KF, Bounds SE, Lin CH, Feng JJ, Lin A, Cheng FC, Crumb WJ, Mitchell R: Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels. J Pharmacol Sci. 2004 Jul;95(3):311-9. [15272206 ]
General Function:
Voltage-gated potassium channel activity involved in sa node cell action potential repolarization
Specific Function:
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:12130714). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:12130714). Homotetrameric channels display rapid activation and slow inactivation (PubMed:8505626, PubMed:12130714). May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation (PubMed:11524461).
Gene Name:
KCNA5
Uniprot ID:
P22460
Molecular Weight:
67227.15 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5051 uMNot AvailableBindingDB 50131434
References
  1. Plouvier B, Beatch GN, Jung GL, Zolotoy A, Sheng T, Clohs L, Barrett TD, Fedida D, Wang WQ, Zhu JJ, Liu Y, Abraham S, Lynn L, Dong Y, Wall RA, Walker MJ: Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation. J Med Chem. 2007 Jun 14;50(12):2818-41. Epub 2007 May 17. [17506538 ]
General Function:
Voltage-gated sodium channel activity
Specific Function:
This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. This sodium channel may be present in both denervated and innervated skeletal muscle.
Gene Name:
SCN4A
Uniprot ID:
P35499
Molecular Weight:
208059.175 Da
References
  1. Desaphy JF, De Luca A, Didonna MP, George AL Jr, Camerino Conte D: Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state-dependent block. J Physiol. 2004 Jan 15;554(Pt 2):321-34. Epub 2003 Nov 7. [14608015 ]