Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides.
The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.
Ellingboe
J W
JW
Division of Exploratory Chemistry, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Spinelli
W
W
Winkley
M W
MW
Nguyen
T T
TT
Parsons
R W
RW
Moubarak
I F
IF
Kitzen
J M
JM
Von Engen
D
D
Bagli
J F
JF
D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D016275:Atrial Function; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D004553:Electric Conductivity; D006325:Heart Atria / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000188:drug therapy; D016276:Ventricular Function; D000096926:Benzenesulfonamides
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D001562:Benzimidazoles; D013424:Sulfanilamides; D013449:Sulfonamides; C073190:WAY 123398; D000096926:Benzenesulfonamides