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.
MeSH terms
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Administration, Oral
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Animals
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Anti-Arrhythmia Agents / chemical synthesis*
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Anti-Arrhythmia Agents / pharmacokinetics
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Anti-Arrhythmia Agents / pharmacology
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Atrial Fibrillation / drug therapy*
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Atrial Fibrillation / etiology
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Biological Availability
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Cell Line
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Crystallography, X-Ray
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Cyclohexanes / chemical synthesis*
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Cyclohexanes / pharmacokinetics
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Cyclohexanes / pharmacology
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Dogs
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Electric Stimulation
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Ethers / chemical synthesis*
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Ethers / chemistry
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Ethers / pharmacology
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Female
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Humans
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Male
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Mice
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Molecular Structure
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Myocardial Ischemia / complications
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Patch-Clamp Techniques
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Potassium Channels, Voltage-Gated / drug effects
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Potassium Channels, Voltage-Gated / physiology
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Pyrrolidinones / chemical synthesis*
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Pyrrolidinones / pharmacokinetics
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Pyrrolidinones / pharmacology
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Sodium Channels / drug effects
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Sodium Channels / physiology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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1-(1-naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane
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Anti-Arrhythmia Agents
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Cyclohexanes
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Ethers
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Potassium Channels, Voltage-Gated
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Pyrrolidinones
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Sodium Channels