Abstract
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 (IC50=2.8×10-7M) with vasodilatory activity (ED50=4.5×10-5M). 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.
