Removal of Human Ether-à-go-goRelated Gene (hERG) K+Channel Affinity through Rigidity:A Case of Clofilium Analogues.

Cardiotoxicityis a side effect that plagues modern drug design and is very oftendue to the off-target blockade of the human ether-à-go-go relatedgene (hERG) potassium channel. To better understand the structuraldeterminants of this blockade, we designed and synthesized a seriesof 40 derivatives of clofilium, a class III antiarrhythmic agent.These were evaluated in radioligand binding and patch-clamp assaysto establish structure–affinity relationships (SAR) for thispotassium channel. Efforts were especially focused on studying theinfluence of the structural rigidity and the nature of the linkerscomposing the clofilium scaffold. It was shown that introducing triplebonds and oxygen atoms in the n-butyl linker of themolecule greatly reduced affinity without significantly modifyingthe pKaof the essential basic nitrogen.These findings could prove useful in the first stages of drug discoveryas a systematic way of reducing the risk of hERG K+channelblockade-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]