Identification

Name
Vernakalant
Accession Number
DB06217
Type
Small Molecule
Groups
Approved, Investigational
Description

Vernakalant was developed by Cardiome Pharma as as an antiarrhythmic drug intended for rapid conversion of atrial fibrillation to sinus rhythm. It acts as an atypical class III antiarrhythmic drug that potentiates its effect in higher heart rates. Intravenous formulation was approved in Europe in September 2010 as Brinavess and in Canada in April 2017. It is an investigational drug under regulatory review by FDA.

Structure
Thumb
Synonyms
  • (3R)-1-((1R,2R)-2-(2-(3,4-dimethoxyphenyl)ethoxy)cyclohexyl)pyrrolidin-3-ol
  • Vernakalant
Product Ingredients
IngredientUNIICASInChI Key
Vernakalant hydrochloride7G4J1ZD9UQ748810-28-8JMHYCBFEEFHTMK-IIUXMCBISA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
BrinavessSolution20 mgIntravenousCardiome Uk Limited2018-01-23Not applicableCanada
International/Other Brands
Kynapid (Cardiome Pharma Corp.)
Categories
UNII
9G468C8B13
CAS number
794466-70-9
Weight
Average: 349.471
Monoisotopic: 349.225308482
Chemical Formula
C20H31NO4
InChI Key
VBHQKCBVWWUUKN-KZNAEPCWSA-N
InChI
InChI=1S/C20H31NO4/c1-23-19-8-7-15(13-20(19)24-2)10-12-25-18-6-4-3-5-17(18)21-11-9-16(22)14-21/h7-8,13,16-18,22H,3-6,9-12,14H2,1-2H3/t16-,17-,18-/m1/s1
IUPAC Name
(3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]pyrrolidin-3-ol
SMILES
COC1=C(OC)C=C(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)C=C1

Pharmacology

Indication

Indicated for the rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults for non-surgery patients that lasts for less than 7 days of duration and post-cardiac surgery patients with atrial fibrillation lasting less than 3 days of duration.

Associated Conditions
Pharmacodynamics

Vernakalant blocks currents in all phases of atrial action potential including atria-specific potassium currents (the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents) and prolongs the refractory period. It dose-dependently prolongs atrial refractoriness, prolongs AV nodal conduction and refractoriness, and slightly prolongs QRS duration without significantly affecting ventricular refractory period. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and is thought to have a low proarrhythmic potential.

Mechanism of action

Vernakalant blocks atrial voltage-gated sodium channels in a dose and frequency-dependent manner and inhibits late sodium current (INa)which confers its effect on intra-atrial conduction. This current blockade enhance and onset of drug action accelerates in higher heart rate as the affinity of vernakalant for INa also increases. Its binding offset is quick once the heart rate slows [A19198]. It also blocks Kv 1.5 channel and its early activating potassium channels (IKur) and inhibits acetylcholine-activated potassium channels (IKAch), which are specific to the atrium and cause prolongation of atrial refractoriness. Vernakalant also blocks Kv4.3 channel and its cardiac transient outward potassium current (Ito), which is involved more with atrial than ventricular refractoriness [A19203]. Vernakalant minimally blocks hERG channels and its rapidly activating/delayed rectifying potassium current (IKr) which accounts for mild QT prolongation. QRS widening due to INa blockade also contributes to QT prolongation [6].

TargetActionsOrganism
ASodium channel protein type 5 subunit alpha
blocker
Human
APotassium voltage-gated channel subfamily A member 5
blocker
Human
APotassium voltage-gated channel subfamily D member 3
blocker
Human
UPotassium voltage-gated channel subfamily H member 2
blocker
Human
Absorption

In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single 10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion of 2 mg/kg with a 15 minute interval between doses [8].

Volume of distribution

Approximately 2L/kg.

Protein binding

Displays low protein binding and the free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml.

Metabolism

Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation is the main metabolism pathway in CYP2D6 poor metabolisers.

Route of elimination

Mainly eliminated via renal excretion.

Half life

Elimination half life in CYP2D6 extensive metabolizers is 3 hours and 5.5 hours in poor metabolizers.

Clearance

The typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg.

Toxicity

Some common unwanted effects include hypotension, ventricular arrhythmias, bradycardia, atrial flutter, dysgeusia, paraesthesia, dizziness and nausea.

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

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Vernakalant.
AbataceptThe metabolism of Vernakalant can be increased when combined with Abatacept.
AbexinostatThe risk or severity of QTc prolongation can be increased when Vernakalant is combined with Abexinostat.
AbirateroneThe metabolism of Vernakalant can be decreased when combined with Abiraterone.
AcebutololThe risk or severity of QTc prolongation can be increased when Vernakalant is combined with Acebutolol.
AceprometazineThe risk or severity of QTc prolongation can be increased when Vernakalant is combined with Aceprometazine.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Vernakalant.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Vernakalant is combined with Acetyldigoxin.
AcrivastineThe risk or severity of QTc prolongation can be increased when Vernakalant is combined with Acrivastine.
AdalimumabThe metabolism of Vernakalant can be increased when combined with Adalimumab.
Food Interactions
Not Available

References

General References
  1. Naccarelli GV, Wolbrette DL, Samii S, Banchs JE, Penny-Peterson E, Stevenson R, Gonzalez MD: Vernakalant--a promising therapy for conversion of recent-onset atrial fibrillation. Expert Opin Investig Drugs. 2008 May;17(5):805-10. doi: 10.1517/13543784.17.5.805 . [PubMed:18447605]
  2. Cheng JW: Vernakalant in the management of atrial fibrillation. Ann Pharmacother. 2008 Apr;42(4):533-42. doi: 10.1345/aph.1K542. Epub 2008 Mar 11. [PubMed:18334607]
  3. Dorian P, Pinter A, Mangat I, Korley V, Cvitkovic SS, Beatch GN: The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans. J Cardiovasc Pharmacol. 2007 Jul;50(1):35-40. [PubMed:17666913]
  4. Orth PM, Hesketh JC, Mak CK, Yang Y, Lin S, Beatch GN, Ezrin AM, Fedida D: RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents. Cardiovasc Res. 2006 Jun 1;70(3):486-96. Epub 2006 Feb 14. [PubMed:16545351]
  5. Savelieva I, Graydon R, Camm AJ: Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines. Europace. 2014 Feb;16(2):162-73. doi: 10.1093/europace/eut274. Epub 2013 Oct 9. [PubMed:24108230]
  6. Camm AJ: The vernakalant story: how did it come to approval in Europe and what is the delay in the U.S.A? Curr Cardiol Rev. 2014 Nov;10(4):309-14. [PubMed:24821654]
  7. Tsuji Y, Dobrev D: Safety and efficacy of vernakalant for acute cardioversion of atrial fibrillation: an update. Vasc Health Risk Manag. 2013;9:165-75. doi: 10.2147/VHRM.S43720. Epub 2013 Apr 23. [PubMed:23637539]
  8. European Medicines Agency Summary of product characteristics [Link]
External Links
KEGG Drug
D06665
PubChem Compound
9930049
PubChem Substance
347827765
ChemSpider
8105680
ChEBI
135956
ChEMBL
CHEMBL2111112
Wikipedia
Vernakalant
ATC Codes
C01BG11 — Vernakalant
AHFS Codes
  • 24:04.04.20 — Class III Antiarrythmics

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedPreventionNonvalvular Atrial Fibrillation2
2, 3CompletedTreatmentAtrial Flutter1
3CompletedTreatmentAtrial Flutter / Nonvalvular Atrial Fibrillation2
3CompletedTreatmentNonvalvular Atrial Fibrillation4
3TerminatedTreatmentNonvalvular Atrial Fibrillation1
4CompletedTreatmentNonvalvular Atrial Fibrillation1
4RecruitingTreatmentParoxysmal Atrial Fibrillation (PAF)1
4Unknown StatusDiagnosticNonvalvular Atrial Fibrillation1
4WithdrawnTreatmentNonvalvular Atrial Fibrillation1
Not AvailableCompletedNot AvailableNonvalvular Atrial Fibrillation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionIntravenous20 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.156 mg/mLALOGPS
logP2.74ALOGPS
logP2.51ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)14.85ChemAxon
pKa (Strongest Basic)9.65ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area51.16 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity98.27 m3·mol-1ChemAxon
Polarizability39.63 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9879
Blood Brain Barrier+0.8078
Caco-2 permeable-0.5127
P-glycoprotein substrateSubstrate0.7152
P-glycoprotein inhibitor INon-inhibitor0.5542
P-glycoprotein inhibitor IIInhibitor0.9347
Renal organic cation transporterNon-inhibitor0.517
CYP450 2C9 substrateNon-substrate0.6724
CYP450 2D6 substrateNon-substrate0.6158
CYP450 3A4 substrateSubstrate0.7177
CYP450 1A2 substrateNon-inhibitor0.6988
CYP450 2C9 inhibitorNon-inhibitor0.8906
CYP450 2D6 inhibitorNon-inhibitor0.5583
CYP450 2C19 inhibitorNon-inhibitor0.5335
CYP450 3A4 inhibitorNon-inhibitor0.6027
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5399
Ames testNon AMES toxic0.7665
CarcinogenicityNon-carcinogens0.9268
BiodegradationNot ready biodegradable0.9758
Rat acute toxicity2.6465 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.688
hERG inhibition (predictor II)Inhibitor0.7926
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 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

Taxonomy

Description
This compound belongs to the class of organic compounds known as tyrosols and derivatives. These are compounds containing a hydroxyethyl group attached to the C4 carbon of a phenol group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenols
Sub Class
Tyrosols and derivatives
Direct Parent
Tyrosols and derivatives
Alternative Parents
Dimethoxybenzenes / Phenoxy compounds / Anisoles / Cyclohexylamines / Alkyl aryl ethers / N-alkylpyrrolidines / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Dialkyl ethers
show 3 more
Substituents
Tyrosol derivative / Dimethoxybenzene / O-dimethoxybenzene / Anisole / Phenoxy compound / Phenol ether / Methoxybenzene / Alkyl aryl ether / Cyclohexylamine / N-alkylpyrrolidine
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Blocker
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 pr...
Gene Name
SCN5A
Uniprot ID
Q14524
Uniprot Name
Sodium channel protein type 5 subunit alpha
Molecular Weight
226937.475 Da
References
  1. Finnin M: Vernakalant: A novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm. 2010 Jul 15;67(14):1157-64. doi: 10.2146/ajhp080501. [PubMed:20592320]
  2. Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483.
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Blocker
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...
Gene Name
KCNA5
Uniprot ID
P22460
Uniprot Name
Potassium voltage-gated channel subfamily A member 5
Molecular Weight
67227.15 Da
References
  1. Eldstrom J, Wang Z, Xu H, Pourrier M, Ezrin A, Gibson K, Fedida D: The molecular basis of high-affinity binding of the antiarrhythmic compound vernakalant (RSD1235) to Kv1.5 channels. Mol Pharmacol. 2007 Dec;72(6):1522-34. Epub 2007 Sep 14. [PubMed:17872968]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Blocker
General Function
Metal ion binding
Specific Function
Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated...
Gene Name
KCND3
Uniprot ID
Q9UK17
Uniprot Name
Potassium voltage-gated channel subfamily D member 3
Molecular Weight
73450.53 Da
References
  1. Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483.
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Blocker
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. Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483.

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase 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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Mao ZL, Wheeler JJ, Clohs L, Beatch GN, Keirns J: Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors. J Clin Pharmacol. 2009 Jan;49(1):17-29. doi: 10.1177/0091270008325148. Epub 2008 Oct 16. [PubMed:18927241]

Drug created on March 19, 2008 10:17 / Updated on December 14, 2018 16:28