New antiarrhythmic agents. 6. Quantitative structure-activity relationships of aminoxylidides.
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.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D002490:Central Nervous System / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D051379:Mice; D013329:Structure-Activity Relationship; D014052:Toluidines / Q000138:chemical synthesis*
D000889:Anti-Arrhythmia Agents; D014052:Toluidines