Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation.
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Plouvier B, Beatch GN, Jung GL, Zolotoy A, Sheng T, Clohs L, Barrett TD, Fedida D, Wang WQ, Zhu JJ, Liu Y, Abraham S, Lynn L, Dong Y, Wall RA, Walker MJ
Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation.
J Med Chem. 2007 Jun 14;50(12):2818-41. Epub 2007 May 17.
- PubMed ID
- 17506538 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Flecainide Sodium channel protein type 5 subunit alpha IC 50 (nM) 6500 N/A N/A Details Lidocaine Sodium channel protein type 5 subunit alpha IC 50 (nM) 108000 N/A N/A Details