Synthesis of novel (aryloxy)propanolamines and related compounds possessing both class II and class III antiarrhythmic activity
| Autor: | Joan M. Lind, Anthony J. Marisca, Gary Phillips, Mark E. Sullivan, Robert P. Gomez, Thomas Kenneth Morgan, Randall Lis, David D. Davey |
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| Rok vydání: | 1990 |
| Předmět: |
Chemical Phenomena
Epinephrine Stereochemistry Purkinje fibers medicine.medical_treatment Adrenergic beta-Antagonists Action Potentials Blood Pressure Pharmacology Antiarrhythmic agent In Vitro Techniques Propanolamines Purkinje Fibers Dogs In vivo Heart Rate Drug Discovery Cardiac conduction Receptors Adrenergic beta medicine Animals Chemistry Chemistry Physical Sotalol Biological activity medicine.anatomical_structure Drug Design Molecular Medicine Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 33(10) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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