新颖的RhoA蛋白小分子抑制剂的设计、合成及其生物活性研究

项目名称： 新颖的RhoA蛋白小分子抑制剂的设计、合成及其生物活性研究

项目编号： No.81202394

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 闫兆威

作者单位： 苏州大学

项目金额： 23万元

中文摘要： 血管痉挛是引起心脑血管疾病重要的病理机制之一，开发针对新靶标和具有新作用机制的缓解血管痉挛药物具有重要的科学意义。RhoA/ROCK通路是非钙离子依赖性细胞收缩的重要传导途径，该通路相关蛋白的高表达或过度激活与血管痉挛的发生有着重要的关系，因此RhoA蛋白可能是一个潜在的药物作用新靶点。本课题组前期针对RhoA蛋白GTP结合域，通过计算机虚拟筛选和生物测试，首次发现3个对RhoA蛋白有较强抑制活性的先导化合物（国内外尚无其它课题组针对RhoA蛋白小分子抑制剂的研究报道），并通过结构优化相继合成了10个衍生物，部分衍生物显示出较好的血管条舒张活性。本课题拟在前期基础上，将新化学实体设计技术与传统的药物化学方法相结合，设计合成活性更强的RhoA抑制剂，并开展促进血管条舒张活性和缓解大鼠SAH-CVS等药理学研究，为研发一种全新的、靶向明确的、能够有效缓解血管痉挛的心脑血管疾病候选药物奠定基础。

中文关键词： RhoA；抑制剂；设计合成；心脑血管痉挛；

英文摘要： Vasospasm plays an important role in the pathogenesis of cardiovascular disease. The R＆D program of new drugs possessing new targets and mechanisms of action to relieve vasospasm will be of great valuable. RhoA/ROCK is a calcium-independent vasoconstriction signal transduction pathway. Over expression and/or activation of key proteins in the RhoA/ROCK signaling transduction pathway plays an important role in the development of vasospasm. Therefore, RhoA protein might be an emerging therapeutic target for intervention. By using structure-based virtual screening in conjunction with chemical synthesis and bioassay,we have previously discovered three novel small molecule RhoA inhibitors which have good RhoA inhibition. To our knowledge, other small molecule RhoA inhibitors have not been reported at present. By further structure modifications,ten derivatives were designed and synthesized accordingly. Part of derivatives showed good vasodilator activity. The aim of the project is to design and synthesize RhoA inhibitors with higher inhibition activity by combining new chemical entities technique with traditional medicinal chemisty method. Furthermore, the relevant pharmacological activities of small molecule RhoA inhibitors in the thoracic aorta rings and rat SAH-CVS models will be evaluated. The research results will

英文关键词： RhoA；Inhibitor；Design and synthesis；Vasospam；