Strategies To Reduce hERG K+ Channel Blockade. Exploring Heteroaromaticity and Rigidity in Novel Pyridine Analogues of Dofetilide

publication · 4 years ago
by Adriaan P. IJzerman, João F. S. Carvalho, Julien Louvel, Maarten L. J. Doornbos, Elisabeth Klaasse, Zhiyi Yu, Johannes Brussee (Leiden University)
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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.

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