Moriya T, Seki M, Takabe S, Matsumoto K, Takashima K, Mori T, Odawara A, Takeyama S
Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
J Med Chem. 1988 Jun;31(6):1197-204. doi: 10.1021/jm00401a021.
A series of 2-aryl and 2-alkyl derivatives of 5-furyl-4-oxazoleacetic acid and their homologues having alkyl groups at the alpha-position of the acids were synthesized and evaluated for their hypolipidemic activities in Sprague-Dawley rats. On the basis of the structure-activity relationships and subacute toxicities, ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate (35) was selected as a candidate compound for development. Compound 35 reduced serum cholesterol and triglyceride levels by 23% and 35%, respectively, at a dose of 0.05% in a diet in normal rats, and it was about 10 times more active in hereditary hyperlipidemic rats (THLR/1) than in normal rats. Compound 35 inhibited platelet aggregation in vitro and also normalized hyperaggregability of hyperlipidemic plasma platelet ex vivo.
合成了一系列5-呋喃基-4-恶唑乙酸的2-芳基和2-烷基衍生物及其在酸的α位带有烷基的同系物，并在Sprague-Dawley大鼠中评估了它们的降血脂活性。基于构效关系和亚急性毒性，选择2-(4-氯苯基)-5-(2-呋喃基)-4-恶唑乙酸乙酯(35)作为开发的候选化合物。在正常大鼠的饮食中，化合物35以0.05%的剂量分别降低血清胆固醇和甘油三酯水平23%和35%，并且在遗传性高脂血症大鼠(THLR/1)中的活性比正常大鼠高约10倍。化合物35在体外抑制血小板聚集，并且还使高脂血症血浆血小板的体外高聚集性恢复正常。
