The data on the activities of all previously described HERG blockers and of the most widely cited I(Kr) blockers were analyzed with respect to the effect of potential charged center(s) and its shielding by surrounding structural elements. The following model was considered: the less shielding of the charged form of the drug occurs, the easier its deprotonation will be and the less potency of the blockade of HERG/I(Kr) channels will be. Tertiary amines which form ammonium ions shielded by two structural fragments of the drug molecule were found to be potent HERG/I(Kr) blockers with IC50 < 1 microM (16 of 19 compounds, 84%). However, if the charged center was found at the molecular periphery as such groups as dimethylamino, N-methylpiperidino, N-methylpiperazino, N-methylpyrrolidino, pyrrolidino, imidazolo and partial periphery (diethylamino), then only moderate potency for HERG blockade with 1 microM < IC50 < 10 microM (8 of 11 compounds; 73%) was observed. Similarly, 27 of 32 weak HERG blockers ( IC50 > 10 microM) were found to be primary or secondary amines, or neutral or very weakly basic compounds. Ions of primary and secondary amines are susceptible to the fast deprotonation of the charged center and they, as well as non-charged compounds, have a low probability of induction of Torsades de Pointes (TdP). Conformational analysis and modeling of the interaction of the charged fragment of the drugs with acetone, a system that mimics a ketone fragment of HERG/I(Kr) channel, supports preference of the conformation with the shielded charged center for potent HERG/I(Kr) blockers. The absence of stereospecificity of HERG/I(Kr) blockade observed in most of the published studies reinforces the importance of charged center shielding as a key parameter. We suggest that the introduction of a hydroxy group at position 3 relative to a tertiary ammonium charged center, or the introduction of hydroxy, alkoxy or amino groups at position 2 relative to the nitrogen center of an aromatic system, should provide easy access of a water molecule to the proton, thereby facilitating deprotonation and thus leading to a moderate or weak HERG/I(Kr) blockade and a reduced risk of TdP.

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RSD1000 is one example of a series of compounds synthesized by Nortran Pharmaceuticals, Inc., to provide selective protection against arrhythmias due to myocardial ischaemia and so providing better therapeutic indices than existing drugs. RSD1019 is an analogue of RSD1000, whose therapeutic indices are better than those of RSD1000. The antiarrhythmic efficacy of RSD1000 and RSD1019 against ventricular arrhythmias induced by myocardial ischaemia were investigated in rats. Doses providing such antiarrhythmic protection were compared with those having effects on the ECG and on electrical stimulation variables and induction of ventricular arrhythmias; such actions are indices of ionic current blockade in normal myocardium. For RSD1019, additional experiments were performed in rabbits and nonhuman primates to rule out species‐specific drug actions. The two compounds were also investigated for their effects on isolated rat hearts and on sodium and potassium currents in isolated rat cardiac myocytes. Analogous studies were performed on potassium currents from transfected potassium channels expressed in human embryonic kidney cells. Lidocaine was used for comparative purposes in several experiments. Drug Dev. Res. 42:198–210, 1997. © 1997 Wiley‐Liss, Inc.

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A series of 2-aminoalkylethers prepared as potential antiarrhythmic agents is described. The present compounds are mixed sodium and potassium ion channel blockers and exhibit antiarrhythmic activity in a rat model of ischemia-induced arrhythmias. Structure-activity studies led to the identification of three compounds 5, 18, and 26, which were selected based on their particular in vivo electrophysiological properties, for studies in two canine atrial fibrillation (AF) models. The three compounds converted AF in both models, but only compound 26 was shown to be orally bioavailable. Resolution of the racemate 26 into its corresponding enantiomers 40 and 41 and subsequent biological testing of these enantiomers led to the selection of (1S,2S)-1-(1-naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane monohydrochloride (41) as a potential atrial selective antiarrhythmic candidate for further development.