title: Mono- and bis(aminomethyl)phenylacetic acid esters as short-acting antiarrhythmic agents. 2.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880.
authors.forename: R J
authors.initials: RJ
authors.lastname: Chorvat
authors.forename: L A
authors.initials: LA
authors.lastname: Black
authors.forename: V V
authors.initials: VV
authors.lastname: Ranade
authors.forename: C
authors.initials: C
authors.lastname: Barcelon-Yang
authors.forename: D M
authors.initials: DM
authors.lastname: Stout
authors.forename: B S
authors.initials: BS
authors.lastname: Brown
authors.forename: H F
authors.initials: HF
authors.lastname: Stampfli
authors.forename: C Y
authors.initials: CY
authors.lastname: Quon
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; D010648:Phenylacetates; D011759:Pyrrolidines; C082818:bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid 1,4-benzodioxanyl-2-methyl ester