Current Topics in Medicinal Chemistry - Volume 8, Issue 13, 2008

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.

This review summarizes current knowledge of the cardiac rapidly activating delayed rectifier potassium current (IKr), and its connection to drug-acquired QT prolongation and the associated risk of ventricular arrhythmia and fibrillation. The molecular characterization of hERG as the structural correlate of IKr and the link between inherited long QT and the KCNH2 gene (hERG), have facilitated mechanistic studies of drug-acquired QT prolongation. The development of high throughput assays to evaluate drug effects on hERG has provided an avenue to determine structure-activity relations (SAR) within chemical series. More than 10 years of collective data and structural considerations support the notion that hERG is an unusually promiscuous target among potassium channels, but that defining SAR within a chemical series is a viable strategy to reduce or eliminate hERG activity. Despite a critical need to minimize drug effects on hERG, one should always keep in mind that hERG is not the only structural correlate of QT prolongation, and that QT prolongation is a sub-optimal biomarker for ventricular arrhythmia and fibrillation.

Sudden death as a side effect of action of non-antiarrhythmic drugs is a major pharmacological safety concern facing the pharmaceutical industry and the health regulatory authorities. A number of drugs have been withdrawn from the market in recent years due to cardiovascular toxicity associated with undesirable blockade of hERG potassium channel. Pharmaceuticals of widely varying structure have been shown to interact with hERG. Defining the molecular features that confer hERG inhibitory activity has therefore become a focus of considerable computational and statistical modeling efforts. Some of the approaches are aimed primarily at filtering out potential hERG blockers in the context of virtual libraries, while others involve understanding structure-activity relationships governing hERG-drug interactions. The ability of models to produce structural hypotheses that can be tested by the project teams has become the key prerequisite driving their organization-wide adoption.

Inhibition of the cardiac IKr current leads to prolongation of the QT interval and to a risk of ventricular arrhythmia. This activity has been observed for a wide range of small molecules and results from their binding to the hERG ion channel. The off-target inhibition of IKr presents a daunting challenge for many medicinal chemistry programs. This review article presents case studies that describe a rang of findings across several projects at Merck. The article begins with a review of findings from the original efforts to identify IKr blockers as antiarrhythmic therapeutics. A discussion follows of in vitro and in vivo assays that have been utilized for the assessment of IKr inhibition. General SAR rules that have been found to be useful guides for diminishing hERG activity in lead compounds are discussed and case studies are presented that illustrate specific observations. The case studies highlight how the issue of hERG antagonism was navigated on four distinct medicinal chemistry programs.

Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

The discovery of small molecule melanin concentrating hormone receptor (MHCr1) antagonists as novel therapeutic agents has been widely pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to induce weight loss in rodent models of obesity, many of these lead compounds have been found to cross react with the hERG channel. This review describes efforts that led to the identification of two sub-series of MCHr1 antagonists with low affinity for the hERG channel. Ultimately, however, the modifications introduced to thwart hERG channel activity resulted in lead compounds with sub-optimal CNS behavior.

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