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 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.
Hester
J B
JB
Upjohn Company, Kalamazoo, Michigan 49001.
Gibson
J K
JK
Cimini
M G
MG
Emmert
D E
DE
Locker
P K
PK
Perricone
S C
SC
Skaletzky
L L
LL
Sykes
J K
JK
West
B E
BE
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D007202:Indicators and Reagents; D013449:Sulfonamides; C067192:ibutilide