title: Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation.
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.
authors.affiliation: Cardiome Pharma Corporation, 6190 Agronomy Road, 6th Floor, Vancouver, British Columbia V6T 1Z3.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Plouvier
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Beatch
authors.forename: Grace L
authors.initials: GL
authors.lastname: Jung
authors.forename: Alexander
authors.initials: A
authors.lastname: Zolotoy
authors.forename: Tao
authors.initials: T
authors.lastname: Sheng
authors.forename: Lilian
authors.initials: L
authors.lastname: Clohs
authors.forename: Terrance D
authors.initials: TD
authors.lastname: Barrett
authors.forename: David
authors.initials: D
authors.lastname: Fedida
authors.forename: Wei Q
authors.initials: WQ
authors.lastname: Wang
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Zhu
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Shlomo
authors.initials: S
authors.lastname: Abraham
authors.forename: Leah
authors.initials: L
authors.lastname: Lynn
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Richard A
authors.initials: RA
authors.lastname: Wall
authors.forename: Michael J A
authors.initials: MJ
authors.lastname: Walker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000209:etiology; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D017202:Myocardial Ischemia / Q000150:complications; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000502:physiology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C521967:1-(1-naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane; D000889:Anti-Arrhythmia Agents; D003510:Cyclohexanes; D004987:Ethers; D024642:Potassium Channels, Voltage-Gated; D011760:Pyrrolidinones; D015222:Sodium Channels