Studies on anti-platelet agents. IV. A series of 2-substituted 4,5-bis(4-methoxyphenyl)pyrimidines as novel anti-platelet agents.
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(-8) M and IC50 = 1.4 x 10(-8) M, 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 3.2 mg/kg in guinea pigs, and 60-70% inhibition 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% inhibitory activity on platelet aggregation induced by A. A. at 6 h after oral administration at 10 mg/kg in this study). Compound 11a also showed vasodilatory activity (ED50 = 5.3 x 10(-6) M, while aspirin has no vasodilatory activity at 6.0 x 10(-4) M).
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
A
A
Tanaka
Y
Y
Motoyama
H
H
Takasugi
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011743:Pyrimidines; D014665:Vasodilator Agents