Synthesis and selective class III antiarrhythmic activity of novel N-heteroaralkyl-substituted 1-(aryloxy)-2-propanolamine and related propylamine derivatives

The synthesis and biological evaluation of a series of novel 1-(aryloxy)-2-propanolamines and several related deshydroxy analogues are described. Compounds 4-29 were prepared and investigated for their class III electrophysiological activity in isolated canine Purkinje fibers and in anesthetized open-chest dogs. None of these compounds showed any class I activity. On the basis of the in vitro data, structure-activity relationships for the series are discussed. Two compounds, N-[4-[2-hydroxy-3-[methyl(2-quinolinylmethyl)amino] propoxy]phenyl]methanesulfonamide (12,WAY-123,223) and N-[2-[[methyl[3-[4-[(methylsulfonyl)amino]phenoxy]propyl] amino]methyl]-6-quinolinyl]-methanesulfonamide (24, WAY-125,971) were identified and characterized as potent and specific class III antiarrhythmic agents in vitro and in vivo. Compound 12 was found to be orally bioavailable, to produce large increases of ventricular fibrillation threshold (VFT), and, in some instances, to restore sinus rhythm from ventricular fibrillation in anesthetized open-chest dogs at a dose of 5 mg/kg (iv). The enantiomers of 12 (i.e., 13 and 14) were synthesized and were found to exhibit similar electrophysiological effects in the Purkinje fiber screen. Compound 24, a propylamine analogue with potency and efficacy comparable to those of UK-68798 (2) and E-4031 (3), was studied in voltage-clamp experiments (isolated cat myocytes) and was found to be a potent and specific blocker of the delayed rectifier potassium current (IK).