Editorial [Hot topic: Medicinal Chemistry Strategies to Minimize hERG Channel Effects 23 May (Guest Editor:Mark T. Bilodeau)]

The discovery of the association between decreased cardiac IKr current and increased risk of fatal ventricular arrhythmia has had a profound impact on the drug discovery process. It has led not only to the removal of drugs from the market but also to the addition of a significant hurdle to the development of new entities. Pharmacologic blockade of the IKr current has been shown to result from binding to the channel underlying the current, hERG. An amazing diversity of molecular structures has been found to bind to the hERG channel with high affinity. As a result, the off-target antagonism of hERG has become an impediment to virtually all medicinal chemistry programs. Navigating around this involves a complex interplay of molecule design and synthesis and in vitro and in vivo assays. The intent of this issue is to review some of the key issues facing medicinal chemists in their struggles to work around this issue. In the first article Lagrutta, Trepakova and Salata review the basic biology of hERG, IKr, QT-interval increase and the relatioship of these factors to each other and to pro-arrhythmic risk. Aronov then provides a review to guide the state of the art in rational drug design around avoiding hERG, providing an overview of models for hERG structure and determinants of binding by small molecules. These reviews are followed by three articles detailing case studies that present the application of these considerations into medicinal chemistry programs. Price et al. present the story of the discovery of Maraviroc, for which modulating hERG affinities was a significant challenge. Bell and Bilodeau then present an overview of a number of experiences at Merck, beginning with the intentional development of IKr blockers as anti-arrhythmic agents, then through several more recent medicinal chemistry programs. Lastly, Judd, Souers and Kym then proivide a case history addressing the hERG issue in the Melanin Concentrating Hormone Receptor 1 Antagonist program at Abbott. The medicinal chemistry around avoiding hERG as an off-target activity has benefited significantly from the development of a better understanding of the biology and structure of the channel and from the development of high-throughput assays. As with the medicinal chemistry of on-target activities, hERG antagonism can at times be rationally guided by binding models and general SAR trends across chemical series and at other times purely by empirical data within a series. As a greater understanding of this critical issue continues to develop, it is hoped that this undesired activity can be avoided in increasingly rational and efficient ways.