Tanaka A, Motoyama Y, Takasugi H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1994 Sep;42(9):1828-34. doi: 10.1248/cpb.42.1828.
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).
本文描述了一系列基于几种环氧化酶（CO）抑制剂的结构分析设计的2-取代4,5-双（4-甲氧基苯基）嘧啶及其作为基于CO抑制的抗血小板药物的衍生物的合成及构效关系。其中，4,5-双（4-甲氧基苯基）-2-吗啉基嘧啶（8）和4,5-双（4-甲氧基苯基）-2-（3,5-二甲基吗啉-4-基）嘧啶（9）对前列腺素中由CO催化花生四烯酸（A.A.）氧化形成的丙二醛在体外产生具有强效抑制活性（分别在10⁻⁸ M时抑制率为73.4%，IC50 = 1.4 x 10⁻⁸ M）。还对某些化合物进行了体内研究。在这些化合物中，4,5-双（4-甲氧基苯基）-2-（1-甲基-1,2,3,6-四氢吡啶-4-基）嘧啶（11a）在体内表现出强效且持久的抗血小板活性，即在豚鼠口服3.2 mg/kg后24小时，11a对A.A.诱导的血小板聚集仍有97%的抑制作用，在较低剂量（1.0 mg/kg）下6小时抑制率为60 - 70%。11a的体内活性是阿司匹林的三倍多（在本研究中，阿司匹林在口服10 mg/kg后6小时对A.A.诱导的血小板聚集的抑制活性为81%）。化合物11a还表现出血管舒张活性（ED50 = 5.3 x 10⁻⁶ M，而阿司匹林在6.0 x 10⁻⁴ M时无血管舒张活性）。
