Novel arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides as platelet aggregation inhibitors. 2. Optimization by quantitative structure-activity relationships.
In the previous paper (Part 1), we described the synthesis and antiplatelet activity of a series of phenyl- and heteroarylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. In this paper, we report the optimization of the platelet aggregation inhibitory activity by an iterative sequence of quantitative structure-activity relationship studies which encompassed synthesis and evaluation of the effects of structure variations at the 1-, 6-, and 7-positions of the heterocyclic system. A model has been established that correctly correlates antiplatelet activity in this series with the partial atomic charges calculated by a local density functional ab initio method. As a result of this study, the experimental platelet aggregation inhibitory activity of the lead compound was improved 300-fold.
Campillo
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Instituto de Química Médica, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain.
Goya
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P
Páez
J A
JA
D000818:Animals; D066298:In Vitro Techniques; D008958:Models, Molecular; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D013829:Thiadiazines