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Executive Summary Information

Compound E-4031
Toxicities Cardiac arrhythmias
Mechanisms E-4031 is a selective Kv11.1 potassium ion channel (aka human Ether-à-go-go-Related Gene, hERG) antagonist.
Comments E-4031 is a preferred reagent for characterizing inhibition of the hERG ion channel in cardiomyocytes.
Feedback Contact Gold Compound Working Group (GCWG)

Leadscope Id LS-183700
CAS 113558-89-7
Pathway DBs
Assay DBs
PubChem CID 3185
Omics DBs
ToxCast Accepted no
Toxic Effect Cardiac arrhythmias
ToxBank Accepted yes
Target Class III antiarrhythmic potassium channel blocker
Toxicities Cardiac arrhythmias

In Vivo Data ? Compound Assessment
Adverse Events ? Cardiotoxicity

E-4031 is an experimental methanesulfonanilide class III antiarrhythmic drug that blocks the hERG potassium channel. hERG controls a critical cardiac IKr repolarizing current involved in initiating terminal cardiac repolarization. Reducing IKr in myocardial cells prolongs the cardiac action potential and thus prolongs the QT-interval. HERG is the only molecular potassium channel target linked to delayed repolarization and a propensity towards arrhythmias. Drugs that block hERG have been linked to Torsade de Pointes (TdP).

Consistent with the role of hERG in controlling repolarization, E-4031 induces a dose- dependent reduction in beat rate but also induces instances of erratic impedance changes reminiscent of arrhythmic muscle fibrillations.

In non-cardiac cells, blocking IKr has a different effect; it increases the frequency of action potentials.


Toxicity Mechanisms ? E-4031 is a type III anti-arrhythmic drug that blocks ion channels encoded by the ether-a-go- go related gene (ERG1 or KCNH1). E-4031 blocks hERG-type potassium channels by binding to the open channels. Its structural target within the hERG-channel is unclear, but some other methanesulfonanilide class III antiarrhythmic drugs are known to bind to the S6 domain or C- terminal of the hERG-channel.

E-4031 is a specific blocker of delayed rectifier current (Ikr). Its selectivity for the small and rapidly activating component of Ikr makes it a useful tool for analyzing K+ channel. It reversibly prolongs action potential duration in guinea pig papillary muscle and isolated ventricular myocytes, without affecting Na + or Ca 2+ inward currents.

Given the important role alterations Ca++ levels can play in the onset of arrhythmia, it was hypothesized that the E-4031-induced erratic impedance changes were reflective of a physiologically meaningful arrhythmia and that modulation of Ca++ trafficking would rescue E- 4031-induced irregularities. To test this hypothesis, nifedipine treatment following the onset of E-4031-induced irregularities was conducted and was able to restore the regular beat rhythm, as observed with both MEA and impedance


Therapeutic Target ? E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type and is used solely for research purposes.



PubMed references

The following resource link will perform a PubMed query for the terms " E-4031 " and "liver toxicity".
E-4031 Search

The following resource link will perform a PubMed query for the terms " E-4031 " and "cardio toxicity".
E-4031 Search

PK-ADME ? Compound Assessment
PK parameters ? Half life in humans is approximately 8.5 h.


-D. Katritsis and A. J. Camm "New class III antiarrhythmic drugs" Eur Heart J (1993) 14 (suppl H): 93-99.
Therapeutic window ? Electrophysiological effects of E 4031, given in a dose ascending manner (1.5, 3.0, and 6.0 micrograms/kg over 5 min followed by 0.1, 0.2, and 0.4 microgram/kg per min for 60 min, respectively) to 19 volunteers At these doses intravenous infusion of E 4031 appears to be safe and well tolerated.


-Katritsis D. et al. "Electrophysiological effects of E 4031, a drug with selective class III properties, in man" Pacing Clin Electrophysiol. 1997 Apr;20(4 Pt 1):930-7.

100 nM E-4031 induced early afterdepolarizations (a trigger for TdP) in stem cell-derived human cardiomyocytes, but not in the rabbit and/or canine Purkinje fibers assay


-Peng, S., et al., "The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes" Journal of Pharmacological and Toxicological Methods (2010), Volume 61, Issue3, Pages 277–286
Metabolically activated ?



Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ?
Proteomics profiles known. ?
Metabonomics profiles known. ?
Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ? Not applicable
Observed IC50 for in vitro cellular toxicity studies. ? In HEK 293 cell lines HERG current was blocked by low concentrations of E-4031 (IC50 7.7 nM), a value close to that reported for I(Kr) in native cardiac myocytes.


-Z Zhou et al. "Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature." Biophys J. 1998 January; 74(1): 230–241.

IC50 for the inhibition of Kv11.1 currents in HEK-293 cells: 500 nM.



IC50 values for binding affinity for the hERG K+ channel in a solution of hERG/HEK293 membranes: 49 nm


-Maris Vilums et al. "Understanding of Molecular Substructures that Contribute to hERG K+ Channel Blockade: Synthesis and Biological Evaluation of E-4031 Analogues" Chem Med Chem 2012, 7, 107–113

IC50 for block of human ERG channels in expression systems: 350 nM



IC50 for inhibition of hERG tail current Qpatch: 25.6 ± 4.3 nM



Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List
Substance stability. ? Store the product tightly sealed at room temperature for 2-3 weeks or at - 20 °C for up to six months.


-Sigma M5060
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Dihydrochloride form: Soluble to 100 mM in water


-Tocris Bioscience (1808)
  • estimated intrinsic solubility : 0.4523 mg/ml
  • estimated solubility in pure water at pH 8.56: 0.5662 mg/ml
  • estimated solubility in water at pH 7.4: 2.1 mg/ml

(Calculations performed using ACD/ PhysChem v 11.0)

Solubility in DMSO 100 times buffer solubility. ? Dihydrochloride form: Soluble to 50 mM in DMSO


-Tocris Bioscience (1808)
Vessel binding properties. ? Undetermined
Vapor pressure. (Non-volatile) ? Non-volatile

Authors of this ToxBank wiki page

David Bower
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