Understanding of Molecular Substructures that Contribute to hERG K+ Channel Blockade: Synthesis and Biological Evaluation of E‐4031 Analogues

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Abstract

Abstract Cardiotoxicity is a common side effect of a large variety of drugs that is often caused by off‐target human ether‐à‐go‐go‐related gene (hERG) potassium channel blockade. In this study, we designed and synthesized a series of derivatives of the class III antiarrhythmic agent E‐4031. These compounds where evaluated in a radioligand binding assay and automated patch clamp assay to establish structure–activity relationships (SAR) for their inhibition of the hERG K + channel. Structural modifications of E‐4031 were made by altering the peripheral aromatic moieties with a series of distinct substituents. Additionally, we synthesized several derivatives with a quaternary nitrogen and modified the center of the molecule by introduction of an additional nitrogen and deletion of the carbonyl oxygen. Some modifications caused a great increase in affinity for the hERG K + channel, while other seemingly minor changes led to a strongly diminished affinity. Structures with quaternary amines carrying an additional aromatic moiety were found to be highly active in radioligand binding assay. A decrease in affinity was achieved by introducing an amide functionality in the central scaffold without directly interfering with the p K a of the essential basic amine. The knowledge gained from this study could be used in early stages of drug discovery and drug development to avoid or circumvent hERG K + channel blockade, thereby reducing the risk of cardiotoxicity, related arrhythmias and sudden death.

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