Studies on Anti-platelet Agents. V. Synthesis and Structure-Activity Relationship of 3-Substituted 5,6-Bis(4-methoxyphenyl)-1,2,4-triazines

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The syntheses and structure-activity relationships of a series of 3-substituted 5,6-bis(4-methoxyphenyl)-1,2,4-triazines as anti-platelet agents based on cyclooxygenase (CO) inhibition are described. Of these compounds, 1-[5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl]carbonyl-4-methylpiperazine (10) exhibited potent CO inhibition in vitro (IC_<50>=2.8×10^<-7>M) with vasodilatory activity (ED_<50>=4.5×10^<-5>M). Compound 10 also showed potent ex vivo activities, completely preventing platelet aggregation induced by arachidonic acid and collagen at 6h after oral administration of 3.2 and 1.0mg/kg. The ex vivo potency of 10 is more than three times that of aspirin. Moreover, 10 demonstrated no gastrointestinal side effect in rats even at 100mg/kg in spite of its potent CO inhibition activity, while aspirin, the most widely-used anti-platelet drug, showed gastrointestinal side effects in a dose-dependent manner (32,100,and 320mg/kg) in our study. These results suggested that 10 is a very attractive candidate for development as an anti-platelet drug since an aspirin-like anti-platelet agent, based on CO inhibition and being free from gastrointestinal side effects, is a major goal of thromboembolic research.
公益社団法人日本薬学会の論文
1994-09-15