Many withdrawn drugs have been shown to block the hERG channel, delaying repolarization of the cardiac action potential and leading to prolongation of the QT interval on an electrocardiogram. This can potentially initiate the arrhythmia known as Torsades de Pointes (TdP) with fatal consequences. While hERG is an important factor for cardiac liability, it is not the only factor. Excitation and relaxation of cardiac muscle is regulated by a variety of different ion channels. Some of these channels are genetically linked with long QT syndrome, suggesting that their modulation by drugs could also produce life-threatening arrhythmias independently of hERG. Conversely, a number of relatively potent hERG channel blockers do not induce TdP. Many of these drugs (e.g. verapamil, amiodarone) have mixed channel blocking action which may ameliorate the effects of hERG blockade. Thus, hERG screening alone may be insufficient to flag potential cardiac liability. Conversely, abandoning promising compounds based on hERG blockade alone may result in failing potentially safe clinical drugs.

#79209 24. apríla 2024 o 8:13