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目的设计并合成单硝酸异山梨酯与阿司匹林组成的孪药,评价该类前药的药理作用和生物活性。方法对单硝酸异山梨酯孪药进行了IR、MS、NMR结构确证,测定了脂水分配系数、血浆酶催化水解速率、体外药理活性、胃肠道刺激性。结果单硝酸异山梨酯孪药(Prodrug1,Prodrug2)的logP值分别为0.89、0.45,在血浆中水解t1/2(2～4min);对二磷酸腺苷(ADP)诱导血小板聚集抑制率为50.9%～52.4%。结论单硝酸异山梨酯组合前药在血浆迅速水解为原药及相关产物,与阿司匹林比较抗血小板活性相近,胃肠道刺激性明显减小。
Objective To design and synthesize the twinning agent of isosorbide mononitrate and aspirin to evaluate the pharmacological action and biological activity of this kind of prodrug. Methods The structure of isosorbide mononitrate was confirmed by IR, MS and NMR. The lipid partition coefficient, the rate of enzymatic hydrolysis of plasma, the pharmacological activity in vitro and the gastrointestinal irritation were determined. Results The logP values of Prodrug 1 and Prodrug 2 were 0.89 and 0.45, respectively, and hydrolyzed in plasma for t1 / 2 (2-4 min). The inhibitory rate of platelet aggregation induced by adenosine diphosphate (ADP) was 50.9 % ~ 52.4%. Conclusions The isosorbide mononitrate combination prodrug rapidly hydrolyzed into the original drug and related products in plasma. Compared with aspirin, anti-platelet prodrugs showed similar anti-platelet activity and gastrointestinal irritation was significantly reduced.