College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Eur J Med Chem. 2009 Dec;44(12):4904-19. doi: 10.1016/j.ejmech.2009.08.002. Epub 2009 Aug 6.
To find new anti-thrombotic agents, a natural amino acid was introduced into the 3-position of anti-platelet aggregation active 3S-tetrahydroisoquinoline-3-carboxylic acid (THIQA), and 20 novel dipeptide derivatives, 3S-tetrahydroisoquinoline-3-carboxyamino acids (6a-t), targeting the intestinal peptide transport system were provided. In vitro anti-platelet aggregation assay of 6a-t indicated that their potencies of inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH) induced platelet aggregations were higher than that of THIQA, and the in vivo anti-thrombotic assay of 6a-t indicated that their potencies of inhibiting thrombogenesis in rats were also higher than that of THIQA. According to MFA based Cerius2 QSAR module, using training/test set of 6a,b,d,g-p/6c,e,f,q and training/test set of 6a-p/6q-t, two equations (r, 0.984 and 0.996) correlating the structures with in vitro or in vivo activity of 6a-t were established.
为了寻找新的抗血栓形成剂，将天然氨基酸引入到抗血小板聚集活性的 3S-四氢异喹啉-3-羧酸（THIQA）的 3-位，提供了 20 种针对肠道肽转运系统的新型二肽衍生物，3S-四氢异喹啉-3-羧基氨基酸（6a-t）。6a-t 的体外抗血小板聚集试验表明，它们抑制二磷酸腺苷（ADP）、花生四烯酸（AA）、血小板激活因子（PAF）和凝血酶（TH）诱导的血小板聚集的效力均高于 THIQA，6a-t 的体内抗血栓形成试验表明，它们抑制大鼠血栓形成的效力也高于 THIQA。根据基于 MFA 的 Cerius2 QSAR 模块，使用 6a、b、d、g-p/6c、e、f、q 的训练/测试集和 6a-p/6q-t 的训练/测试集，建立了两个与 6a-t 的体外或体内活性相关的方程（r，0.984 和 0.996）。
