Synthesis of novel (aryloxy)propanolamines and related compounds possessing both class II and class III antiarrhythmic activity.
Several (aryloxy)propanolamines and related compounds (i.e. 5-13, 16-18, 20-24, 27-33, 35, 37-39, 41, and 42) were synthesized and investigated for their class III electrophysiological activity and class II (beta-blocking) effects with use of in vitro and in vivo models. Structure-activity relationships are discussed for a series of 30 compounds. A number of these compounds prolonged the action potential duration at 95% repolarization of isolated canine cardiac Purkinje fibers by 20% (C20APD95) at concentrations of less than 1.0 microM, with no significant effects on cardiac conduction. beta-Adrenergic receptor binding studies showed that some of these compounds were 2-20 times more potent for cardiac beta 1 receptors than for beta 2 receptors. In particular, compounds 32, 41, 1, and especially (S)-1 were found to be orally active class III agents in anesthetized mongrel dogs (1 or 3 mg/kg, id) and efficacious at suppressing programmed electrical stimulation induced arrhythmias in halothane-anesthetized dogs. The profile of these compounds was similar to that found for sotalol. Compound (S)-1, which was more potent than sotalol in the PES study and equieffective in the halothane/epinephrine dog model, is being investigated further as a combined class III/II antiarrhythmic agent.
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Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
Morgan
T K
TK
Marisca
A J
AJ
Gomez
R P
RP
Lind
J M
JM
Davey
D D
DD
Phillips
G B
GB
Sullivan
M E
ME
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004285:Dogs; D015195:Drug Design; D004837:Epinephrine / Q000037:antagonists & inhibitors; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D011412:Propanolamines / Q000138:chemical synthesis* / Q000378:metabolism; D011690:Purkinje Fibers / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D004837:Epinephrine