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Exploring Chemical Substructures Essential for hERG K+ Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues |
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| Authors: | Shagufta Dr. Dong Guo Elisabeth Klaasse Dr. Henk de Vries Johannes Brussee Dr. Lukáš Nalos Martin B. Rook Dr. Marc A. Vos Prof. Marcel A. G. van der Heyden Dr. Adriaan P. IJzerman Prof. |
| Affiliation: | 1. Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands), Fax: (+31)?71‐527‐4565;2. Department of Medical Physiology, DH&L, UMC Utrecht, Yalelaan 50, 3584 CM Utrecht (The Netherlands) |
| 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. |
| Keywords: | cardiotoxicity dofetilide hERG ion channels radioligand binding assays structure– activity relationships |