N-[(.omega.-Amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with class III antiarrhythmic activity

N-[4-[4-(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamid e, (E)-2-butenedioate (2:1) salt (ibutilide fumarate, 2E), has been found to have Class III antiarrhythmic activity. In an in vitro rabbit heart tissue preparation designed to evaluate the cardiac electrophysiology of potential antia...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-01, Vol.34 (1), p.308-315
Main Authors: Hester, Jackson B, Gibson, J. Kenneth, Cimini, Madeline G, Emmert, D. Edward, Locker, Paula K, Perricone, Salvatore C, Skaletzky, Louis L, Sykes, Julie K, West, Bruce E
Format: Article
Language:English
Subjects:
Animals
Anti-Arrhythmia Agents - chemical synthesis
Arrhythmias, Cardiac - drug therapy
Dogs
Female
Heart - drug effects
Heart - physiology
Heart Ventricles - drug effects
In Vitro Techniques
Indicators and Reagents
Magnetic Resonance Spectroscopy
Male
Molecular Structure
Myocardial Contraction - drug effects
Myocardial Infarction - drug therapy
Rabbits
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
Ventricular Function
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Summary:N-[4-[4-(Ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamid e, (E)-2-butenedioate (2:1) salt (ibutilide fumarate, 2E), has been found to have Class III antiarrhythmic activity. In an in vitro rabbit heart tissue preparation designed to evaluate the cardiac electrophysiology of potential antiarrhythmic agents, it selectively prolongs the effective refractory period of papillary muscle. In vivo it increases the ventricular refractory period of the canine heart and prevents the ventricular arrhythmias induced by programmed electrical stimulation 3-9 days after a myocardial infarction. This paper describes the synthesis of 2E and a series of related compounds. The in vitro evaluation of the cardiac electrophysiology of these compounds has allowed us to determine the structural requirements for Class III antiarrhythmic activity in this series. Evaluation of the antiarrhythmic activity of 2E and one of the more potent analogues on the late postinfarction ventricular arrhythmias induced by programmed electrical stimulation of the canine myocardium is also described. This activity is compared with that of the Class III antiarrhythmic agent sotalol. Compound 2E appears to be as effective and 10-30 times more potent than sotalol in this model.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00105a048