Studies on Anti-platelet Agents. IV. A Series of 2-Substituted 4, 5-Bis(4-methoxyphenyl)pyrimidines as Novel Anti-platelet Agents

Abstract

The syntheses and structure-activity relationships of a series of 2-substituted 4, 5-bis(4-methoxyphenyl)pyrimidines, designed on the basis of structural analyses of several cyclooxygenase (CO) inhibitors, and their derivatives as anti-platelet agents based on CO inhibition are described. Among them, 4, 5-bis(4-methoxyphenyl)-2-morpholinopyrimidine (8) and 4, 5-bis(4-methoxyphenyl)-2-(3, 5-dimethylmorpholin-4-yl)pyrimidine (9) showed potent inhibitory activity on malondialdehyde, formed by the CO-catalyzed oxygenation of arachidonic acid (A.A.) in prostanoids, production in vitro (73.4% inhibition at 10^-8M and IC₅₀=1.4×10^-8M, respectively). Certain compounds were also examined in ex vivo studies. Of these compounds, 4, 5-bis(4-methoxyphenyl)-2-(1-methyl-1, 2, 3, 6-tetrahydropyrid-4-yl)pyrimidine (11a) exhibited potent and long-lasting anti-platelet activity ex vivo, that is, 11a showed 97% inhibition of platelet aggregation induced by A.A. even 24h after oral administration of 3.2mg/kg in guinea pigs, and 60-70% inhibition at 6h after lower doses (1.0mg/kg). The ex vivo activity of 11a is more than three times that of aspirin (aspirin showed 81% inhibitory activity on platelet aggregation induced by A. A. at 6h after oral administration at 10mg/kg in this study). Compound 11a also showed vasodilatory activity (ED₅₀=5.3×10^-6M, while aspirin has no vasodilatory activity at 6.0×10^-4M).