New aminocarboxamides with class III anti-arrhythmic activity.
In the search for new anti-arrhythmic substances we discovered the class III activity of aminocarboxamides. These compounds show a prolongation of the effective refractory period. With some of them the prolongation is more pronounced after faster than after slower stimulation of the guinea pig papillary muscle. They should therefore be of interest in the treatment of cardiac arrhythmias after myocardial infarction and atrial fibrillation. The chemical synthesis, the structure-activity relationships of the new derivatives, their efficacy on the action potential duration (APD) and the effective refractory period (ERP) in vitro of isolated guinea pig papillary muscles are described and discussed in this paper. Since AWD 160-275 (13) and AWD 23-111 (14) exerted a pronounced APD90 and ERP prolongation at faster stimulation, they were selected for further electrophysiological characterization in vitro and in vivo. Anti-arrhythmic and pro-arrhythmic effects were determined in several animal models in comparison with dofetilide, sematilide, and sotalol. 13 was found to be effective in preventing programmed electrical 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.
Poppe
H
H
Department of Chemistry, Corporate R & D, Arzneimittelwerk Dresden GmbH, Radebeul, Germany.
Schindler
R
R
Sauer
W
W
Marx
D
D
Bartsch
R
R
Kaverina
N V
NV
Lichoscherstow
A M
AM
Sokolov
S F
SF
Lyskovtsev
V V
VV
Seredenin
S B
SB
Borisenko
S A
SA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002415:Cats; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; C104135:N-(dicyclohexylcarbamoylmethyl)-N-(3-diethylaminopropyl)-4-nitrobenzamide hydrochloride