QT prolongation through hERG K⁺ channel blockade: Current knowledge and strategies for the early prediction during drug development

Abstract

Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.

Exploring Chemical Substructures Essential for hERG K+ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues

“…Reduction in hERG activity was observed with polar and bulky groups such as NH 2 , NHSO 2 CH 3 and NHCOCH 3 groups. Interestingly, compounds bearing a NHSO 2 CH 3 group exhibited much higher affinity than analogues bearing the isosteric substituent NHCOCH 3 .…”

“…Synthesis of dofetilide analogues with different substituents on the benzene ring (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Reagents and conditions: a) 1,2-dibromoethane, NaOH, TBAB, EtOH, reflux; b) phenethylamine or 4-substituted phenethylamine, K 2 CO 3 , CH 3 Analogues with varying chain lengths (77-81) were prepared following the same reaction conditions (see Scheme 5) as described for 30-45 in Scheme 1. Commercially available 4-nitrophenol (7) was alkylated with the corresponding dibromo alkanes 70-72 to afford the intermediates 13, 73 and 74.…”

“…However, nonantiarrythmic drugs and their metabolites may also cause prolongation of the QT interval in the electrocardiogram, which increases risk for torsade de pointes, a ventricular arrhythmia causing syncope, ventricular fibrillation and sudden death. [1][2][3] In recent years, this type of cardiac toxicity has become a major pharmacological safety concern for the pharmaceutical industry and health regulatory agencies. [4] A number of drugs were withdrawn from the market or failed in late-stage clinical trials because cardiac arrhythmia was a side effect of treatment.…”

A Composite Model for hERG Blockade

“…Among them are KCNQ1, the gene that encodes the potassium channel relevant for I ks , a smaller depolarizing K + current, and SCN5A, the gene that encodes the cardiac Na + channel. [17,18] However, all clinically relevant cases of drug-induced LQTS could be traced back to either hERG blockade [19,20] or interference with hERG trafficking to the cell surface. [21] Cardiac polarization/repolarization is managed by different ion channels.…”

Activation Gating of hERG Potassium Channels

“…The physiological importance of hERG is illustrated by the discovery that block of the pore by medications or loss of channel function due to inherited mutations carries an increased risk of sudden cardiac death (2). Therefore, there is considerable interest in gaining further insight into the structural basis of hERG gating and drug binding (3,4).…”