Guo D, Klaasse E, de Vries H, Brussee J, Nalos L, Rook MB, Vos MA, van der Heyden MA, Ijzerman AP
Exploring Chemical Substructures Essential for hERG K(+) Channel Blockade by Synthesis and Biological Evaluation of Dofetilide Analogues. [JOURNAL ARTICLE]
ChemMedChem 2009 Sep 1.
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.
More from this journal |
