Class III Antiarrhythmic Activity of Novel Substituted 4-benzamides and Sulfonamides

Article abstract of DOI:10.1021/jm00082a011

The synthesis and Class III antiarrhythmic activity of a series of 4-<(methylsulfonyl)amino>benzamides and sulfonamides are described.Selected compounds shown 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 the 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 (I_K) at concentrations that cause significant prolongation of action potential duration.