Structure-activity relationships and electrophysiological effects of short-acting amiodarone homologs in guinea pig isolated heart

Antiarrhythmic agents with amiodarone- like electrophysiological actions, b ut with a more favorable pharmacokinetic profile than amiodarone would be e xtremely useful for the treatment of many tachyarrhythmias. We designed a s eries 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 si ze and branching of the ester group. The magnitude and time course of elect rophysiological effects caused by methyl (ATI-2001), ethyl (ATI-2010), isop ropyl (ATI-2064), sec- butyl (ATI-2042), and neopentyl (ATI-2054) homologs, and their common metabolite (ATI-2000) were investigated in guinea pig iso lated heart. In paced hearts (atrial cycle length = 300 ms), each homolog ( 1 mM) 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 t he metabolite prolonged the AH interval. The relative rank order for the ho mologs to lengthen ventricular repolarization (MAPD(90)) was ATI-2042 great er than or equal to 2001 = 2010 = 2064 > 2054 greater than or equal to 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 th e ATI compounds. The different structure-activity relationships among the a miodarone homologs may have important consequences for further development of amiodarone-like antiarrhythmic agents.