n-(3-4-dimethoxyphenyl)-n-(3-((2-(3-4-dimethoxyphenyl)ethyl)methylamino)propyl)-4-nitrobenzamide-hydrochloride and Myocardial-Ischemia

BRL-32872 is a new antiarrhythmic drug with balanced class-III and class-IV actions as categorized by the Vaughan-Williams classification. BRL-32872 blocks the rapid component of the cardiac delayed rectifier potassium channel IK(r) (IC(50) = 28 nM) and its molecular correlate HERG ("Human-ether-a-go-go related gene," IC(50) of 19.8 nM in cell lines) at low concentrations. It also inhibits the L-type calcium current (ICa) at higher concentrations (IC(50) = 2.8 microM). This dual concentration-dependent profile of action at higher concentrations may possibly prevent "torsades de pointes" ventricular arrhythmias, which is a dangerous side effect of many other class-III antiarrhythmic drugs. With BRL-32872, an excessive prolongation of the action potential duration and consecutive QTc prolongation is prevented by a concentration-dependent increase of calcium channel block, resulting in the so-called "bell-shaped" profile of antiarrhythmic drug action. BRL-32872 is very effective in the treatment of ventricular arrhythmias in animal models of cardiac ischemia. In the ischemic hearts of animals the drug significantly reduced early afterdepolarization and ventricular tachycardia. The antiarrhythmic effect of BRL-32872 has not yet been demonstrated in humans.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzamides; Cation Transport Proteins; DNA-Binding Proteins; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Myocardial Ischemia; Myocardium; Papillary Muscles; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Purkinje Fibers; Tachycardia, Ventricular; Trans-Activators; Transcriptional Regulator ERG

The antifibrillatory potential of BRL-32872, a novel antiarrhythmic compound with K+ and Ca2+ channel blocking activities, was examined in a minipig model of ischemia-induced arrhythmia. The effects of intravenous (i.v.) BRL-32872 (0.3 and 1.0 mg/kg, n = 8), dofetilide (0.3 mg/kg, n = 8), and flecainide (2.0 mg/kg, n = 8), were investigated on the incidence of ventricular fibrillation (VF) during a 20-min occlusion of the left anterior descending coronary artery (LAD). Ischemia-induced VF occurred in 6 of 9 vehicle-treated pigs. BRL-32872 reduced the incidence of ischemic VF to 13% at 0.3 mg/kg (p < 0.05) and to 0% at 1.0 mg/kg (p < 0.01). Dofetilide also prevented the occurrence of VF (0%, p < 0.01) In contrast, flecainide did not reduce the incidence of VF (63%). Indeed, flecainide shortened the time to onset of VF from 17 +/- 1 min in the vehicle group to 10 +/- 1 min (p < 0.001). The antifibrillatory effects of BRL-32872 and dofetilide were associated with a prolongation of QT interval on ECG. Flecainide did not prolong repolarization, but slowed the ventricular conduction velocity, as shown by significant increases in PR and QRS intervals. During early reperfusion, 1 of 8 surviving pigs in each group treated with BRL-32872 and 4 of 8 in the dofetilide group developed VF. This study demonstrated an antifibrillatory effect of BRL-32872 associated with prolonged ventricular repolarization and showed enhanced efficacy over dofetilide on reperfusion arrhythmias which is most likely a consequence of its Ca2+ blocking activity.

Topics: Analysis of Variance; Animals; Anti-Arrhythmia Agents; Benzamides; Disease Models, Animal; Flecainide; Injections, Intravenous; Myocardial Ischemia; Myocardial Reperfusion Injury; Phenethylamines; Sulfonamides; Swine; Swine, Miniature; Ventricular Fibrillation