Studies on anti-platelet agents. V. Synthesis and structure-activity relationship of 3-substituted 5,6-bis(4-methoxyphenyl)-1,2,4-triazines.
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-methylpi perazine (10) exhibited potent CO inhibition in vitro (IC50 = 2.8 x 10(-7) M) with vasodilatory activity (ED50 = 4.5 x 10(-5) M). Compound 10 also showed potent ex vivo activities, completely preventing platelet aggregation induced by arachidonic acid and collagen at 6 h after oral administration of 3.2 and 1.0 mg/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 100 mg/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 320 mg/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.
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
A
A
Tanaka
H
H
Sakai
T
T
Ishikawa
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*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D014227:Triazines