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 ...

s of the hERG-type.

Chemistry

E-4031 is a synthesized

toxin A toxin is a naturally occurring poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919), derived ...

that is a methanesulfonanilide class III antiarrhythmic drug.

Target

E-4031 acts on a specific class of

voltage-gated potassium channel Voltage-gated potassium channels (VGKCs) are potassium channel, transmembrane channels specific for potassium and Voltage-gated ion channel, sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a ...

s 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, carboxy 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 t ...

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

cardiac action potential Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generati ...

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, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...

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 subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

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

References

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