STUDIES ON ANTIPLATETLET AGENTS .4. A SERIES OF 2-SUBSTITUTED 4,5-BIS(4-METHOXYPHENYL)PYRIMIDINES AS NOVEL ANTIPLATETLET AGENTS

The syntheses and structure-activity relationships of a series of 2-su bstituted 4,5-bis(4-methoxyphenyl)pyrimidines, designed on the basis o f structural analyses of several cyclooxygenase (CO) inhibitors, and t heir derivatives as anti-platelet agents based on CO inhibition are de scribed. Among them, 4,5-bis(4-methoxyphenyl)-2-morpholinopyrimidine ( 8) and 4,5-bis(4-methoxyphenyl)-2-(3,5-dimethyl (9) showed potent inhi bitory activity on malondialdehyde, formed by the CO-catalyzed oxygena tion of arachidonic acid (A.A.) in prostanoids, production in vitro (7 3.4% inhibition at 10(-8) and IC50 = 1.4 x 10(-8)M, respectively). Cer tain compounds were also examined in ex vivo studies. Of these compoun ds, -(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 24 h after oral administration of 3.2 mg/kg in guinea pigs, and 60-70% in hibition at 6 h after lower doses (1.0 mg/kg). The ex vivo activity of 11a is more than three times that of aspirin (aspirin showed 81% inhi bitory activity on platelet aggregation induced by A. A. at 6 h after oral administration at 10 mg/kg in this study). Compound 11a also show ed vasodilatory activity(ED(50) = 5.3 x 10(-6) M, while aspirin has no vasodilatory activity at 6.0 x 10(-4) M).