Referenced in: none

Automatically associated channels: Kv11.1

Title: Exploring chemical substructures essential for HERG k(+) channel blockade by synthesis and biological evaluation of dofetilide analogues.

Authors: , Dong Guo, Elisabeth Klaasse, Henk de Vries, Johannes Brussee, Lukás Nalos, Martin B Rook, Marc A Vos, Marcel A G van der Heyden, Adriaan P Ijzerman

Journal, date & volume: , 2009 Oct , 4, 1722-32

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19725081

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.