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非肽类纤维蛋白原受体拮抗剂(Ⅱ): N-取代-O-对甲脒苯氧乙基-L-酪氨酸甲酯的合成与抗血小板聚集活性研究

许天林*, 蒋巡天**, 华维一, 倪沛洲, 裴咏梅*   

  1. 中国药科大学新药研究中心, 南京 210009;
  • 收稿日期:1998-11-10 修回日期:1999-06-01 出版日期:1999-12-15 发布日期:1999-12-15
  • 通讯作者: 许天林*, 蒋巡天**, 裴咏梅*

Synthesis and Antiaggregating Activity of Nonpeptide Fibrinogen Receptor Antagonists (Ⅱ): N-Substituted-O-(4-Amidinophenoxy) Ethyl-L-Tyrosine Methyl Ester

Xu Tianlin*, Jiang Xuntian**, Hua Weiyi, Ni Peizhou, Pei Yongmei*   

  1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009
  • Received:1998-11-10 Revised:1999-06-01 Online:1999-12-15 Published:1999-12-15
  • Contact: Xu Tianlin*, Jiang Xuntian**, Pei Yongmei*

摘要:

本文通过对存在于纤维蛋白原和其它内源性整合素内精氨酸-甘氨酸-天冬氨酸(RGD)序列结构的分析, 在前文N-取代-O-对甲脒苯胺基羰甲基-L-酪氨酸甲酯的基础上, 为了探讨空间臂极性的变化对化合物活性的影响, 以氧乙基代替胺基羰甲基设计并合成了一系列含有酪氨酸骨架的非肽类模拟物。本文还测定了化合物抗ADP诱导的兔血小板聚集的抑制率, 结果表明, 12个化合物中有9个在10-6 mol·L-1时显示有一定的抑制作用, 其中Ii 抑制作用最强。

关键词: 非肽类纤维蛋白原受体拮抗剂, 结构设计, 合成, 酪氨酸, 抗血小板聚集活性

Abstract:

A series of nonpeptide fibrinogen receptor antagonists were designed andsynthesized by mimicking the structure of Arg-Gly-Asp (RGD) sequences in fibrinogen. In order toexplore the effect of spacer polarity on inhibitory activity, 12 N-substituted-O-(4-amidinophenoxy) ethyl-L-tyrosine methyl esters have been synthesized with the less polar dioxyethylene spacer insteadof the aminocarbonyl methyl in our previous report. The inhibitory effects of 12 target compoundscontaining tyrosine skeleton for adenosine 5-diphosphate (ADP) induced platelet aggregation inrabbit platelet-rich plasma were evaluated utilizing a turbidometric technique and 9 compoundsshowed inhibitory action at the concentration as low as 1×10-6 mol·L-1, of which Ii has the bestactivity.

Key words: Nonpeptide fibrinogen receptor antagonists, Nonpeptide fibrinogen receptor antagonists, Structure design, Structure design, Synthesis, Synthesis, Tyrosine, Tyrosine, Antiaggregating activity, Antiaggregating activity

Supporting: *Present Address: Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850
**Present Address:Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031