Mono- and bis(aminomethyl)phenylacetic acid esters as short-acting antiarrhythmic agents. 2.
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.
Chorvat
R J
RJ
Department of Medicinal Chemistry, Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880.
Black
L A
LA
Ranade
V V
VV
Barcelon-Yang
C
C
Stout
D M
DM
Brown
B S
BS
Stampfli
H F
HF
Quon
C Y
CY
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
D000889:Anti-Arrhythmia Agents; D010648:Phenylacetates; D011759:Pyrrolidines; C082818:bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid 1,4-benzodioxanyl-2-methyl ester