A Class of 3S-2-Aminoacyltetrahydro-β-carboline-3-carboxylic Acids: Their Facile Synthesis, Inhibition for Platelet Activation, and High in Vivo Anti-Thrombotic Potency

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• 作者：Jiawang Liu ; Xueyun Jiang ; Ming Zhao ; Xiaoyi Zhang ; Meiqing Zheng ; Li Peng ; Shiqi Peng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 22, 2010
• 年：2010
• 卷：53
• 期：8
• 页码：3106-3116
• 全文大小：885K
• 年卷期：v.53,no.8(April 22, 2010)
• ISSN：1520-4804

文摘

3S-Tetrahydro-β-carboline-3-carboxylic acid (TCCA) effectively inhibits ADP-induced platelet activation. This paper used TCCA as a lead, modified its 2-position with amino acids, and provided 20 novel 3S-2-aminoacyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids (5a−t). With the in vitro assay, it was demonstrated that this modification diminished the IC₅₀ values from 701 nM of TCCA to 10 nM of 5a−t. With the in vivo assay, it was demonstrated that this modification reduced the efficacious dose from 5.0 μmol/kg of TCCA to 0.1 μmol/kg of 5a−t. Comparing the Cerius² based conformation of them with that of their analogues, the 3-position modified TCCA, it was suggested that the comparatively unfolded conformation was one of the important factors of enhancing the in vivo antithrombotic potency.