StrategiesTo Reduce hERG K+Channel Blockade.Exploring Heteroaromaticity and Rigidity in Novel Pyridine Analoguesof Dofetilide.

Drug-inducedblockade of the human ether-a-go-go-related gene K+channel(hERG) represents one of the major antitarget concernsin pharmaceutical industry. SAR studies of this ion channel have shedlight on the structural requirements for hERG interaction but mostimportantly may reveal drug design principles to reduce hERG affinity.In the present study, a novel library of neutral and positively chargedheteroaromatic derivatives of the class III antiarrhythmic agent dofetilidewas synthesized and assessed for hERG affinity in radioligand bindingand manual patch clamp assays. Structural modifications of the pyridinemoiety, side chain, and peripheral aromatic moieties were evaluated,thereby revealing approaches for reducing hERG binding affinity. Inparticular, we found that the extra rigidity imposed close to thepositively charged pyridine moiety can be very efficient in decreasinghERG affinity. [ABSTRACT FROM AUTHOR]