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Synthesis and Biological Studies of Novel 2-Aminoalkylethers as Potential Antiarrhythmic Agents for the Conversion of Atrial Fibrillation

2007; American Chemical Society; Volume: 50; Issue: 12 Linguagem: Inglês

10.1021/jm0604528

1520-4804

Bertrand Plouvier, Gregory N. Beatch, Grace L. Jung, Alexander Zolotoy, Tao Sheng, Lilian Clohs, Terrance D. Barrett, David Fedida, Wei Q. Wang, Jeff J. Zhu, Yuzhong Liu, S. Thomas Abraham, Leah Lynn, Ying Dong, Richard A. Wall, Michael Walker,

Ion channel regulation and function

A series of 2-aminoalkylethers prepared as potential antiarrhythmic agents is described. The present compounds are mixed sodium and potassium ion channel blockers and exhibit antiarrhythmic activity in a rat model of ischemia-induced arrhythmias. Structure−activity studies led to the identification of three compounds 5, 18, and 26, which were selected based on their particular in vivo electrophysiological properties, for studies in two canine atrial fibrillation (AF) models. The three compounds converted AF in both models, but only compound 26 was shown to be orally bioavailable. Resolution of the racemate 26 into its corresponding enantiomers 40 and 41 and subsequent biological testing of these enantiomers led to the selection of (1S,2S)-1-(1-naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane monohydrochloride (41) as a potential atrial selective antiarrhythmic candidate for further development.