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New antiarrhythmic agents. 6. Quantitative structure-activity relationships of aminoxylidides.

Abstract
The synthesis and pharmacological evaluation of primary and tertiary aminoxylidides with the amino group in the 2-7 position of the acyl chain are described. 2,6-Xylidine was acylated with haloacyl halides and converted to the target compounds by direct amination or by the Gabriel procedure. Alternatively, 2,6-xylidine was coupled with keto acids, and the ketoxylidides were converted to the amines by reductive amination. The target compounds were evaluated in mice both for antiarrhythmic efficacy against chloroform-induced tachycardia and for central nervous system toxicity. Experimentally determined values of partition coefficients and pKa values were used for quantitative structure-activity analyses. While the antiarrhythmic activity could be described as a function of log P alone, the CNS toxicity was best described as a function of both log P and pKa. The results suggest that antiarrhythmic potency can be increased by increasing lipophilicity, while the therapeutic index can be improved by increasing the pKa.
AuthorsP A Tenthorey, A J Block, R A Ronfeld, P D McMaster, E W Byrnes
JournalJournal of medicinal chemistry (J Med Chem) Vol. 24 Issue 7 Pg. 798-806 (Jul 1981) ISSN: 0022-2623 [Print] United States
PMID7277383 (Publication Type: Journal Article)
Chemical References
  • Anti-Arrhythmia Agents
  • Toluidines
Topics
  • Animals
  • Anti-Arrhythmia Agents (chemical synthesis)
  • Central Nervous System (drug effects)
  • Chemical Phenomena
  • Chemistry
  • Female
  • Mice
  • Structure-Activity Relationship
  • Toluidines (chemical synthesis)

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