Antiarrhythmic agents with
amiodarone-like electrophysiological actions, but with a more favorable pharmacokinetic profile than
amiodarone would be extremely useful for the treatment of many
tachyarrhythmias. We designed a series of
amiodarone homologs with an alkyl
ester group at position 2 of the benzofurane moiety. It was hypothesized that the electrophysiological and pharmacokinetic properties of these compounds are closely related to the size and branching of the
ester group. The magnitude and time course of electrophysiological effects caused by methyl (ATI-2001), ethyl (ATI-2010), isopropyl (ATI-2064), sec-butyl (ATI-2042), and neopentyl (ATI-2054) homologs, and their common metabolite (ATI-2000) were investigated in guinea pig isolated heart. In paced hearts (atrial cycle length = 300 ms), each homolog (1 microM) was infused for 90 min followed by a 90-min washout. The stimulus-to-atrium (St-A), atrium-to-His bundle (AH), His bundle-to-ventricle (HV), QRS, and QT intervals, and ventricular monophasic action potential duration at 90% repolarization (MAPD(90)) were measured every 10 min.
ATI-2001 and ATI-2064 significantly lengthened the St-A, HV, and QRS intervals, whereas
ATI-2042 and ATI-2054 prolonged only the St-A interval. All compounds except the metabolite prolonged the AH interval. The relative rank order for the homologs to lengthen ventricular repolarization (MAPD(90)) was
ATI-2042 > or = 2001 = 2010 = 2064 > 2054 > or = 2000. The metabolite was electrophysiologically inactive. Thus, modification of the benzofurane moiety
ester group size and branching markedly altered the magnitude and time course of the electrophysiological effects caused by the ATI compounds. The different structure-activity relationships among the
amiodarone homologs may have important consequences for further development of
amiodarone-like antiarrhythmic agents.