New aminocarboxamides with class III anti-arrhythmic activity

In the search for new anti-arrhythmic substances we discovered the class II I activity of aminocarboxamides. These compounds show a prolongation of the effective refractory period. With some of them the prolongation is more pr onounced after faster than after slower stimulation of the guinea pig papil lary muscle. They should therefore he of interest in the treatment of cardi ac arrhythmias after myocardial infarction and atrial fibrillation. The che mical synthesis, the structure-activity relationships of the new derivative s, their efficacy on the action potential duration (APD) and the effective refractory period (ERP) in vitro of isolated guinea pig papillary muscles a re described and discussed in this paper. Since AWD 160-275 (13) and AWD 23 -111 (14) exerted a pronounced APD(90) and ERP prolongation at faster stimu lation, they were selected for further electrophysiological characterizatio n in vitro and in vivo. Anti-arrhythmic and pro-arrhythmic effects were det ermined in several animal models in comparison with dofetilide. sematilide, and sotalol. 13 was found to be effective in preventing programmed electri cal stimulation-induced arrhythmias in anaesthetized dogs and may therefore contribute to the therapy of dysrhythmias after myocardial infarction. The pro-arrhythmic effect of 14, investigated in a model of triggered activity in chloralose-anaesthetized rabbits under methoxamine infusion, is low in comparison with other class III anti-arrhythmics.