【作者】 张洪旺；

【导师】 郭宗儒；

【作者基本信息】 中国协和医科大学 ， 药物化学， 2000， 博士

【摘要】 血栓形成是心血管疾病的病因之一，在形成血栓的各种因素中血小板聚集起重要作用，其中纤维蛋白原结合糖蛋白Ⅱb／Ⅲa(GPⅡb／Ⅲa)受体是血小板凝聚最后的共同的一步，因此阻断纤维蛋白原(fibrinogen)和GPⅡb／Ⅲa的结合可以抑制各种激动剂(如胶原，凝血酶等)介导的血小板聚集，所以GPⅡb／Ⅲa拮抗剂有巨大的市场价值。本论文共合成药效团为脒苯基和羧基的两类化合物：(1)线形化合物：药效团之间以线性骨架支撑的化合物；(2)苯二氮(艹卓)化合物：药效团之间以苯二氮(艹卓)为支撑骨架的化合物。(1)线形化合物在设计和合成已有GPⅡb／Ⅲa拮抗剂的me-too化合物之前，用比较分子力场分析法(CoMFA)对文献报道的16个化合物建立了三维定量构效关系模型，提示该类化合物的立体场，静电场的分布对活性的影响。依据所得的3D-QSAR模型和Me-too药物分子设计原理，以处于三期临床研究的Sibrafiban和Lamifiban为模型分子，通过改变氨基酸侧链，设计并合成具有知识产权的新化合物，其中GPI-3，GPI-4，GPI-8，GPI-9，GPI-12，GPI-13，GPI-15，GPI-23，GPI-26等具有和模型化合物相似的活性，GPI-3，GPI-4，GPI-22，GPI-23进行了体内活性评价，结果表明测试化合物在体内可以保持相当的稳定性，在较长的时间内对血小板有较高程度的抑制，优于模型分子，进一步的实验正在进行中。(2)苯二氮(艹卓)化合物苯二氮(艹卓)化合物的设计以SB公司开发的Lotrafiban为先导物，合成化合物的药理评价正在进行中。本论文共合成120个化合物，其中新化合物71个，目标化合物36个。更多还原

【Abstract】 The thrombus formation is one of the causes of the cardiovascular diseases, in which process platelet aggregation involves the central event mediated by the binding of the plasma protein fibrinogen to the glycoprotein IIb/IIIa receptor (GPIIb/IIIa) on the surface of activated platelet. This binding is final common pathway for platelet aggregation. Therefore GPIIb/IIIa antagonists can completely inhibit platelet aggregation regardless of the various agonist(collagen, thrombin et al) involved. So GPIIb/IIIa receptor antagonists have a huge market value.Two series of compounds with amidinophenyl and carbonyl groups were synthesized in this dissertation:(1)linear compounds: the two pharmacophores being separated by a linear skeleton; (2)benzodiazepine compounds: the pharmacophores being attached on the benzodiazepine scaffold. (1)linear compoundsBefore design and synthesis of me-too compounds of existing GPIIb/IIIa antagonists, a 3D-QSAR analysis was conducted with 16 reported compounds using CoMFA. The result indicated both steric and electrostatic fields affect the inhibitory activity.Based on 3-D QSAR model and me-too drug design principle, the new compounds with proprietary were designed and synthesized through the change of the side chains of amino acids of Sibrafiban and Lamifiban which were investigated in clinical phase III and used as model compounds. Among the synthesized target compounds, GPI-3, GPI-4, GPI-8, GPI-9, GPI-12, GPI-13, GPI-15, GPI-22 and GPI-23 showed the activities as potent as the model compounds. And GPI-3, GPI-4, GPI-12, GPI-13 were further assayed in vivo. The result demonstrated these compounds maintained the metabolic stability and inhibited platelet aggregation in high level with a prolonged duration of activity, superior to the model compounds. The further experiments were being carried on.(2) benzodiazepine compoundsThe benzodiazepine compounds were designed and synthesized by using Lotrafiban as lead compound. The biological assays are in test.In this dissertation, 120 compounds were synthesized, in which 71 compounds were novel and 36 compounds is the target molecules and identified.更多还原