Journal
CHEMMEDCHEM
Volume 4, Issue 10, Pages 1722-1732Publisher
WILEY-BLACKWELL
DOI: 10.1002/cmdc.200900203
Keywords
cardiotoxicity; dofetilide; hERG; ion channels; radioligand binding assays; structure-activity relationships
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Funding
- Dutch Top Institute Pharma [D2-201]
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In this study we followed anew 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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