Drug discovery vs hERG

Abstract

A number of marketed drugs have been withdrawn and numerous clinical and preclinical compounds discontinued due to prolongation of the time interval between Q and T waves of the electrocardiogram (long QT syndrome). Drug-induced QT interval prolongation, which may lead to life-threatening cardiac arrhythmia torsades de pointes (TdP), has been linked to blockade of a cardiac potassium channel, a product of the human ether-a`-go-go-related gene (hERG). Consequently, drug discovery efforts across the pharmaceutical industry have been utilizing hERG in vitro assays to predict and minimize the risk of QT prolongation. This chapter discusses in silico, in vitro, ex vivo, and in vivo methods employed to measure blockade of hERG and QT prolongation, as well as regulatory recommendations, and medicinal chemistry strategies utilized to circumvent interactions with hERG.