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

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 pKa 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. Go‐go dancing with hERG! Evaluation of derivatives of E‐4031, a class III antiarrhythmic agent, provides practical information on the molecular determinants for hERG K+ channel blockade. Chemical features that are likely to increase affinity for the hERG K+ channel can be omitted ( ) during drug development; likewise, structural elements that reduce affinity ( ) could be included to potentially circumvent cardiotoxicity related attrition at a later stage.