E-4031 is an experimental class III antiarrhythmic drug that blocks

potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of c ...

s of the hERG-type.

Chemistry

E-4031 is a synthetized

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...

that is a methanesulfonanilide class III antiarrhythmic drug.

Target

E-4031 acts on a specific class of voltage-gated potassium channels mainly found in the heart, the hERG channels. hERG channels (Kv11.1) mediate the I_Kr current, which repolarizes the myocardial cells. The hERG channel is encoded by ether-a-go-go related gene (hERG).

Mode of action

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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

of the hERG-channel. Reducing I_Kr in myocardial cells prolongs the

cardiac action potential The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...

and thus prolongs the QT-interval. In non-cardiac cells, blocking I_kr has a different effect: it increases the frequency of action potentials.

Toxicity

As E-4031 can prolong the QT-interval, it can cause lethal

arrhythmias Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

Therapeutic use

E-4031 is solely used for research purposes. So far, one

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

has been conducted to test the effect of E-4031 on prolongation of the QT-interval.

References

{{Antiarrhythmic agents HERG blocker Potassium channel blockers Pyridines Piperidines Aromatic ketones Sulfonamides