Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation.

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.

The mechanism of atrial antiarrhythmic action of RSD1235.

INTRODUCTION: RSD1235 is a novel drug recently shown to convert AF rapidly and safely in patients.(1) Its mechanism of action has been investigated in a rat model of ischemic arrhythmia, along with changes in action potential (AP) morphology in isolated rat ventricular myocytes and effects on cloned channels. METHODS AND RESULTS: Ischemic arrhythmias were inhibited with an ED50 of 1.5 micromol/kg/min, and repolarization times increased with non-significant effects on PR and QRS durations. AP prolongation was observed in rat myocytes at low doses, with plateau elevation and a reduction in the AP overshoot at higher doses. RSD1235 showed selectivity for voltage-gated K+ channels with IC50 values of 13 microM on hKv1.5 (1 Hz) versus 38 and 30 microM on Kv4.2 and Kv4.3, respectively, and 21 microM on hERG channels. RSD1235 did not block IK1 (IC50 > 1 mM) nor ICa,L (IC50= 220 microM) at 1 Hz in guinea pig ventricular myocytes (n = 4-5). The drug displayed mild (IC50= 43 microM at 1 Hz) open-channel blockade of Nav1.5 with rapid recovery kinetics after rate reduction (10-->1 Hz, 75% recovery with tau= 320 msec). Nav1.5 blocking potency increased with stimulus frequency from an IC50= 40 microM at 0.25 Hz, to an IC50= 9 microM at 20 Hz, and with depolarization increasing from 107 microM at -120 mV to 31 microM at -60 mV (1 Hz). CONCLUSIONS: These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency- and voltage-dependent block of INa.

Physicochemical determinants for drug induced blockade of HERG potassium channels: effect of charge and charge shielding.

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.