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.
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Authors | P A Tenthorey, A J Block, R A Ronfeld, P D McMaster, E W Byrnes |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 24
Issue 7
Pg. 798-806
(Jul 1981)
ISSN: 0022-2623 [Print] United States |
PMID | 7277383
(Publication Type: Journal Article)
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Chemical References |
- Anti-Arrhythmia Agents
- Toluidines
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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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