Synthesis and cardiac electrophysiological activity of aryl-substituted derivatives of the class III antiarrhythmic agent sematilide. Potential class I/III agents
| Autor: | Klaus Nickisch, Mark E. Sullivan, Thomas M. Argentieri, Thomas Kenneth Morgan, Gary B. Phillips, Ronald A. Wohl, Robert P. Gomez, Joan M. Lind |
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| Rok vydání: | 1990 |
| Předmět: |
Tertiary amine
Chemical Phenomena Purkinje fibers Guinea Pigs Action Potentials Stimulation Pharmacology In Vitro Techniques Procainamide Purkinje Fibers chemistry.chemical_compound Structure-Activity Relationship Dogs In vivo Drug Discovery medicine Animals Ouabain Chemistry Aryl Sematilide Arrhythmias Cardiac Class III antiarrhythmic agent Electrophysiology medicine.anatomical_structure Biochemistry Drug Design cardiovascular system Molecular Medicine Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 33(2) |
| ISSN: | 0022-2623 |
| Popis: | Twelve novel derivatives of the selective class III antiarrhythmic agent sematilide were prepared in an attempt to incorporate both class I and class III electrophysiological properties into a single molecule. Electrophysiological activity was determined by standard microelectrode techniques in canine cardiac Purkinje fibers. Initial assessment of class I efficacy was carried out in a ouabain-induced arrhythmia model in guinea pigs. All of the compounds prolonged action potential duration in Purkinje fibers (class III activity), and three were active against ouabain-induced arrhythmias (class I activity). Selected compounds were evaluated further in dogs for efficacy against arrhythmias occurring 24 h following coronary ligation (automatic arrhythmias) and induced by using programmed electrical stimulation techniques (reentrant arrhythmias). The most effective compounds from the series are 3g and -j, which were effective in both canine models. Molecular modeling and structure-activity relationships are discussed. |
| Databáze: | OpenAIRE |
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