title: Strategies to reduce HERG K+ channel blockade. Exploring heteroaromaticity and rigidity in novel pyridine analogues of dofetilide.
abstract: Drug-induced blockade of the human ether-a-go-go-related gene K(+) channel (hERG) represents one of the major antitarget concerns in pharmaceutical industry. SAR studies of this ion channel have shed light on the structural requirements for hERG interaction but most importantly may reveal drug design principles to reduce hERG affinity. In the present study, a novel library of neutral and positively charged heteroaromatic derivatives of the class III antiarrhythmic agent dofetilide was synthesized and assessed for hERG affinity in radioligand binding and manual patch clamp assays. Structural modifications of the pyridine moiety, side chain, and peripheral aromatic moieties were evaluated, thereby revealing approaches for reducing hERG binding affinity. In particular, we found that the extra rigidity imposed close to the positively charged pyridine moiety can be very efficient in decreasing hERG affinity.
authors.affiliation: Leiden Academic Center for Drug Research, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: João F S
authors.initials: JF
authors.lastname: Carvalho
authors.forename: Julien
authors.initials: J
authors.lastname: Louvel
authors.forename: Maarten L J
authors.initials: ML
authors.lastname: Doornbos
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Klaasse
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yu
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D013449:Sulfonamides / 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