Mono- and bis(aminomethyl)phenylacetic acid esters as short-acting antiarrhythmic agents. 2

• Published in: Journal of medicinal chemistry Vol. 36; no. 17; pp. 2494 - 2498
• Main Authors: Chorvat, Robert J, Black, Lawrence A, Ranade, Vasant V, Barcelon-Yang, Cynthia, Stout, David M, Brown, Barry S, Stampfli, Herman F, Quon, Check Y
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.1993
• Subjects: Animals; Anti-Arrhythmia Agents - chemical synthesis; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - pharmacology; Dogs; Guinea Pigs; Half-Life; Humans; Phenylacetates - chemical synthesis; Phenylacetates - pharmacokinetics; Phenylacetates - pharmacology; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00069a007

The synthesis, antiarrhythmic activity, and blood hydrolysis properties of a series of mono- and bis(aminomethyl)phenylacetic acid esters related to a previously reported class Ic antiarrhythmic agent (ACC-9358) are described. Of the various oxa-, aza-, thia-, and carbacyclic esters initially prepared in the bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid series, the 1,4-benzodioxanyl-2-methyl(3q) and the thienyl-2-methyl(31) esters were evaluated in vivo for antiarrhythmic efficacy. In addition, a number of monoappended phenylacetic esters of 3q with or without the 4-hydroxy group were also prepared for evaluation of antiarrhythmic, lipophilic, and metabolic properties. Of these compounds, 3q possessed the most desirable pharmacological and pharmacokinetic profile.