Propafenone

Common Name

Propafenone Description

Propafenone is only found in individuals that have used or taken this drug. It is an antiarrhythmia agent that is particliarly effective in ventricliar arrhythmias. It also has weak beta-blocking activity. The drug is generally well tolerated. [PubChem]The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Structure

Synonyms

Value Source 1-(2-(2-Hydroxy-3-(propylamino)propoxy)phenyl)-3-phenyl-1-propanoneChEBI 2-(2'-Hydroxy-3'-propylaminopropoxy)-omega-phenylpropiophenoneChEBI PropafenonaChEBI PropafenonumChEBI Abbott brand OF propafenone hydrochlorideMeSH Aliud brand OF propafenone hydrochlorideMeSH ArythmolMeSH Knoll brand OF propafenone hydrochlorideMeSH Merck dura brand OF propafenone hydrochlorideMeSH Propafenone hydrochloride, (R)-isomerMeSH Propafenone, (+-)-isomerMeSH Propafenone, (R)-isomerMeSH Q-Pharm brand OF propafenone hydrochlorideMeSH SA-79MeSH Apotex brand OF propafenone hydrochlorideMeSH Azupharma brand OF propafenone hydrochlorideMeSH FenoprainMeSH Hydrochloride, propafenoneMeSH Kendrick brand OF propafenone hydrochlorideMeSH NistakenMeSH PintoformMeSH Propafenon alMeSH Propafenon hexalMeSH RytmogenatMeSH SA 79MeSH TAD brand OF propafenone hydrochlorideMeSH Alpharma brand OF propafenone hydrochlorideMeSH apo-PropafenoneMeSH BaxarytmonMeSH CuxafenonMeSH Juta brand OF propafenone hydrochlorideMeSH JutanormMeSH NorfenonMeSH Propafenon mindenMeSH Propafenone hydrochlorideMeSH Propafenone hydrochloride, (S)-isomerMeSH Propafenone, (S)-isomerMeSH RythmolMeSH RytmonormMeSH Hexal brand OF propafenoneMeSH ProlecofenMeSH PropamerckMeSH rytmo-PurenMeSH

Chemical Formlia

C₂₁H₂₇NO₃ Average Molecliar Weight

341.444 Monoisotopic Molecliar Weight

341.199093735 IUPAC Name

1-{2-[2-hydroxy-3-(propylamino)propoxy]phenyl}-3-phenylpropan-1-one Traditional Name

propafenone CAS Registry Number

54063-53-5 SMILES

InChI Identifier

InChI Key

JWHAUXFOSRPERK-UHFFFAOYSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as linear 1,3-diarylpropanoids. These are organic compounds with a structure based on a C6-C3-C6 skeleton, where the two benzene rings are not linked together. Kingdom

Chemical entities Super Class

Organic compounds Class

Phenylpropanoids and polyketides Sub Class

Linear 1,3-diarylpropanoids Direct Parent

Linear 1,3-diarylpropanoids Alternative Parents

Alkyl-phenylketones

Butyrophenones

Phenoxy compounds

Phenol ethers

Benzoyl derivatives

Aryl alkyl ketones

Alkyl aryl ethers

Secondary alcohols

1,2-aminoalcohols

Dialkylamines

Organopnictogen compounds

Organic oxides

Hydrocarbon derivatives

Substituents

Linear 1,3-diarylpropanoid

Alkyl-phenylketone

Butyrophenone

Phenylketone

Benzoyl

Phenol ether

Phenoxy compound

Aryl ketone

Aryl alkyl ketone

Alkyl aryl ether

Benzenoid

Monocyclic benzene moiety

1,2-aminoalcohol

Secondary alcohol

Ketone

Secondary amine

Secondary aliphatic amine

Ether

Organic oxide

Organonitrogen compound

Organooxygen compound

Organic nitrogen compound

Organopnictogen compound

Alcohol

Hydrocarbon derivative

Amine

Organic oxygen compound

Aromatic homomonocyclic compound

Molecliar Framework

Aromatic homomonocyclic compounds External Descriptors

secondary alcohol (CHEBI:63619 )

secondary amino compound (CHEBI:63619 )

aromatic ketone (CHEBI:63619 )

Ontology Status

Expected but not Quantified Origin

Drug

Biofunction

Anti-Arrhythmia Agents

Application

Pharmaceutical

Cellliar locations

Membrane

Physical Properties State

Solid Experimental Properties

Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water Solubility7.58e-03 g/LNot Available LogP3.2Not Available

Predicted Properties

Property Value Source Water Solubility0.0076 mg/mLALOGPS logP3.1ALOGPS logP3.54ChemAxon logS-4.7ALOGPS pKa (Strongest Acidic)14.09ChemAxon pKa (Strongest Basic)9.63ChemAxon Physiological Charge1ChemAxon Hydrogen Acceptor Count4ChemAxon Hydrogen Donor Count2ChemAxon Polar Surface Area58.56 ŲChemAxon Rotatable Bond Count11ChemAxon Refractivity100.21 m³·mol^-1ChemAxon Polarizability39.75 ųChemAxon Number of Rings2ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

Spectra Spectra

Spectrum Type Description Splash Key Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

Biological Properties Cellliar Locations

Membrane

Biofluid Locations

Blood

Urine

Tissue Location

Not Available Pathways

Not Available Normal Concentrations

Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01182

21059682

details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01182

21059682

details

Abnormal Concentrations

Not Available Associated Disorders and Diseases Disease References

None Associated OMIM IDs

None External Links DrugBank ID

DB01182 DrugBank Metabolite ID

Not Available Phenol Explorer Compound ID

Not Available Phenol Explorer Metabolite ID

Not Available FoodDB ID

Not Available KNApSAcK ID

Not Available Chemspider ID

4763 KEGG Compound ID

C07381 BioCyc ID

Not Available BiGG ID

Not Available Wikipedia Link

Propafenone NuGOwiki Link

HMDB15313 Metagene Link

HMDB15313 METLIN ID

Not Available PubChem Compound

4932 PDB ID

Not Available ChEBI ID

63619

Product: Cephalotaxlen

References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References Not Available

Enzymes

General function:

Involved in monooxygenase 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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.

Gene Name:

CYP3A4

Uniprot ID:

P08684

Molecular weight:

57255.585

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 ]

General function:

Involved in monooxygenase 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.

Gene Name:

CYP2C9

Uniprot ID:

P11712

Molecular weight:

55627.365

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 ]

General function:

Involved in monooxygenase activity

Specific function:

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.

Gene Name:

CYP2D6

Uniprot ID:

P10635

Molecular weight:

55768.94

References

1. Botsch S, Gautier JC, Beaune P, Eichelbaum M, Kroemer HK: Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol. 1993 Jan;43(1):120-6. [PubMed:8423765 ]
2. 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 ]

General function:

Involved in monooxygenase 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.

Gene Name:

CYP1A2

Uniprot ID:

P05177

Molecular weight:

58406.915

References

1. Botsch S, Gautier JC, Beaune P, Eichelbaum M, Kroemer HK: Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol. 1993 Jan;43(1):120-6. [PubMed:8423765 ]
2. 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 ]

General function:

Involved in monooxygenase 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti-cancer drug paclitaxel (taxol).

Gene Name:

CYP2C8

Uniprot ID:

P10632

Molecular weight:

55824.275

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 ]

General function:

Involved in ion channel activity

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). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Gene Name:

KCNH2

Uniprot ID:

Q12809

Molecular weight:

126653.5

References

1. Mergenthaler J, Haverkamp W, Huttenhofer A, Skryabin BV, Musshoff U, Borggrefe M, Speckmann EJ, Breithardt G, Madeja M: Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel. Naunyn Schmiedebergs Arch Pharmacol. 2001 Apr;363(4):472-80. [PubMed:11330342 ]
2. Arias C, Gonzalez T, Moreno I, Caballero R, Delpon E, Tamargo J, Valenzuela C: Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels. Cardiovasc Res. 2003 Mar;57(3):660-9. [PubMed:12618228 ]
3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

General function:

Involved in ion 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. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential in the electrocardiogram

Gene Name:

SCN5A

Uniprot ID:

Q14524

Molecular weight:

226937.5

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 ]

Transporters

General function:

Involved in ATP binding

Specific function:

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

Gene Name:

ABCB1

Uniprot ID:

P08183

Molecular weight:

141477.3

References

1. Schmid D, Ecker G, Kopp S, Hitzler M, Chiba P: Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol. 1999 Nov 1;58(9):1447-56. [PubMed:10513988 ]
2. Bachmakov I, Rekersbrink S, Hofmann U, Eichelbaum M, Fromm MF: Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2005 Mar;371(3):195-201. Epub 2005 Apr 15. [PubMed:15900513 ]
3. Singh P, Paul K: Studies of interactions between uracil-based hybrid molecules and P-glycoprotein–search for multidrug resistance modulators. Bioorg Med Chem. 2006 Nov 1;14(21):7183-6. Epub 2006 Jul 14. [PubMed:16843673 ]
4. Woodland C, Verjee Z, Giesbrecht E, Koren G, Ito S: The digoxin-propafenone interaction: characterization of a mechanism using renal tubular cell monolayers. J Pharmacol Exp Ther. 1997 Oct;283(1):39-45. [PubMed:9336306 ]
5. Tmej C, Chiba P, Huber M, Richter E, Hitzler M, Schaper KJ, Ecker G: A combined Hansch/Free-Wilson approach as predictive tool in QSAR studies on propafenone-type modulators of multidrug resistance. Arch Pharm (Weinheim). 1998 Jul-Aug;331(7-8):233-40. [PubMed:9747179 ]

PMID: 26658258

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