Removal of human ether-à-go-go related gene (hERG) K+ channel affinity through rigidity: a case of clofilium analogues.
Cardiotoxicity is a side effect that plagues modern drug design and is very often due to the off-target blockade of the human ether-à-go-go related gene (hERG) potassium channel. To better understand the structural determinants of this blockade, we designed and synthesized a series of 40 derivatives of clofilium, a class III antiarrhythmic agent. These were evaluated in radioligand binding and patch-clamp assays to establish structure-affinity relationships (SAR) for this potassium channel. Efforts were especially focused on studying the influence of the structural rigidity and the nature of the linkers composing the clofilium scaffold. It was shown that introducing triple bonds and oxygen atoms in the n-butyl linker of the molecule greatly reduced affinity without significantly modifying the pKa of the essential basic nitrogen. These findings could prove useful in the first stages of drug discovery as a systematic way of reducing the risk of hERG K(+) channel blockade-induced cardiotoxicity.
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University , P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Julien
J
Louvel
João F S
JF
Carvalho
Zhiyi
Z
Yu
Marjolein
M
Soethoudt
Eelke B
EB
Lenselink
Elisabeth
E
Klaasse
Johannes
J
Brussee
Adriaan P
AP
Ijzerman
D000889:Anti-Arrhythmia Agents / Q000737:chemistry*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; C022799:clofilium