| Title | Exploring Chemical Substructures Essential for hERG K(+) Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues. | | Author(s) | Shagufta, Guo D, Klaasse E, de Vries H, Brussee J, Nalos L, Rook MB, Vos MA, van der Heyden MA, Ijzerman AP | | Institution | 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. | | Source | ChemMedChem 2009 Sep 1. | | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19725081 |
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