基于骨架迁越和药效团的新型凝血酶抑制剂的设计与合成

项目名称： 基于骨架迁越和药效团的新型凝血酶抑制剂的设计与合成

项目编号： No.21272277

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 徐云根

作者单位： 中国药科大学

项目金额： 80万元

中文摘要： 凝血酶抑制剂是治疗血栓性疾病的重要药物。达比加群酯是一种新型的非肽类直接凝血酶抑制剂，具有疗效好、出血风险小等优点，它是一种前药，其活性成分是达比加群。HY-023065是本课题组以达比加群为先导物，在分析其与凝血酶结合方式的基础上，利用骨架迁越方法，保留脒基和羧基药效团，将其核心结构苯并咪唑骨架转换为1,2,3,4-四氢苯并[4,5]咪唑并[1,2-a]吡嗪骨架而得到的新型凝血酶抑制剂。本项目首先以HY-023065为先导物，设计两个系列衍生物；其次将HY-023065分子中的4-脒基苄基从2位移至1位以进一步改善与凝血酶的匹配性，并设计两个系列衍生物。本项目共设计合成65个新型小分子化合物，通过体外凝血酶抑制活性、体内抗血栓作用、出血风险和初步药代动力学评价，期望获得1至2个抗血栓功效好、出血风险小、具有自主知识产权的新型抗凝血候选化合物，拓宽非肽类凝血酶抑制剂的结构类型和构效关系。

中文关键词： 凝血酶抑制剂；抗血栓作用；1;2;3;4-四氢苯并[4;5]咪唑[1;2-a]吡嗪；川芎嗪；合成

英文摘要： Thrombin inhibitors are important drugs for treatment of thrombotic diseases. Dabigatran etexilate is a novel non-peptide direct thrombin inhibitor which possesses many therapeutic advantages such as good efficacy, small bleeding risk, etc. Dabigatran etexilate is a prodrug, its active ingredient is dabigatran. HY-023065 is a new thrombin inhibitors, which derived from dabigatran using a scaffold hopping approach based on analysis of the binding mode between dabigatran and thrombin, by converted benzimidazole skeleton (the core structure of dabigatran) to 1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2-a]pyrazine structure, while retaining key pharmacophore amidine and carboxyl group. In this project, firstly, we are about to choose HY-023065 as the lead compound to design two series of derivatives. Secondly, we intend to move the 4-amidine benzyl group in HY-023065 molecule from position 2 to position 1 in order to improve the matching ability between new molecule and thrombin, and design two series of derivatives. We plan to synthesize 65 new small molecule compounds in all. On the basis of a series of pharmacological tests including in vitro thrombin inhibitory activity, in vivo antithrombotic effect, bleeding risk and preliminary pharmacokinetic evaluations, this project, on the one hand, will be expected to get on

英文关键词： thrombin inhibitors；antithrombotic effect；1;2;3;4-tetrahydrobenzo[4;5]imidazo[1;2-a]pyrazine；ligustrazine；synthesis