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Exploring Chemical Substructures Essential for hERG K+ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues

Shagufta Shagufta, Dong Guo, Elisabeth Klaasse, Henk de Vries, Johannes Brussee, Lukáš Nalos, Martin B. Rook, Marc A. Vos, Marcel A. G. van der Heyden, Adriaan P. IJzerman

Open publisher page 26 citations

Abstract

In this study we followed a new approach to analyze molecular substructures required for hERG channel blockade. We designed and synthesized 40 analogues of dofetilide (1), a potent hERG potassium channel blocker, and established structure-activity relationships (SAR) for their interaction with this important cardiotoxicity-related off-target. Structural modifications to dofetilide were made by diversifying the substituents on the phenyl rings and the protonated nitrogen and by varying the carbon chain length. The analogues were evaluated in a radioligand binding assay and SAR data were derived with the aim to specify structural features that give rise to hERG toxicity.

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What this paper is about

In this study we followed a new approach to analyze molecular substructures required for hERG channel blockade. We designed and synthesized 40 analogues of dofetilide (1), a potent hERG potassium channel blocker, and established structure-activity relationships (SAR) for their interaction with this important cardiotoxicity-related off-target. Structural modifications to dofetilide were made by diversifying the substituents on the phenyl rings and the protonated nitrogen and by varying the carbon chain length. The analogues were evaluated in a radioligand binding assay and SAR data were derived with the aim to specify structural features that give rise to hERG toxicity.

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Available abstract

In this study we followed a new approach to analyze molecular substructures required for hERG channel blockade. We designed and synthesized 40 analogues of dofetilide (1), a potent hERG potassium channel blocker, and established structure-activity relationships (SAR) for their interaction with this important cardiotoxicity-related off-target. Structural modifications to dofetilide were made by diversifying the substituents on the phenyl rings and the protonated nitrogen and by varying the carbon chain length. The analogues were evaluated in a radioligand binding assay and SAR data were derived with the aim to specify structural features that give rise to hERG toxicity.

Key concepts: hERG, Dofetilide, Chemistry, Potassium channel blocker, Blockade, Cardiotoxicity, Potassium channel, Pharmacology

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Exploring Chemical Substructures Essential for hERG K+ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues — Research Paper | ScholarLens