“…A number of hERG channel pharmacophores have been developed, with the key determinants being a protonated basic nitrogen surrounded by several aromatic or hydrophobic groups. ,,– ,– It has been found that a hydrogen-bond (H-bond) acceptor or an electron-withdrawing atom located at the periphery of the molecule may also contribute to high-affinity binding to hERG. ,,,,, Based on these studies, a number of lead optimization approaches to avoid hERG blockage have been proposed. These include subtle peripheral structural modifications, removing distal aryl groups, adding an acidic function or its bioisostere, decreasing lipophilicity, decreasing p K a of the most basic nitrogen, introducing geometric constraints, and changing molecular shape. – ,,,– Although it has been shown that all of these approaches work in particular cases, none of them is a panacea. The main drawback of these approaches is that, as well as decreasing potency at the hERG channel, they more than often simultaneously decrease the potency at the intended target. – …”