title: Exploring chemical substructures essential for HERG k(+) channel blockade by synthesis and biological evaluation of dofetilide analogues.
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.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands).
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Klaasse
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Lukás
authors.initials: L
authors.lastname: Nalos
authors.forename: Martin B
authors.initials: MB
authors.lastname: Rook
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: D002460:Cell Line; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide