【作者】 刘娜；

【导师】 李阳；

【作者基本信息】 天津大学 ， 应用化学， 2016， 硕士

【摘要】 多发性硬化症(multiple sclerosis,MS)是以中枢神经系统白质脱髓鞘和炎细胞浸润为特点的慢性自身免疫性疾病,致残率高。研究表明,Rho激酶是一种具有多重作用的药物靶点。在中枢神经系统的各种疾病中可以观察到Rho/ROCK异常激活。ROCK活动失调是许多神经系统疾病的重要发病机制。抑制Rho激酶可以调节免疫、抗炎、促进神经突触生长和神经干细胞增生分化、损伤后神经功能恢复。法舒地尔作为唯一上市的Rho激酶抑制剂,对MS有明确的治疗作用。以法舒地尔为先导化合物为先导化合物设计合成法舒地尔的衍生物以期得到对Rho激酶抑制活性较高的Rho激酶抑制剂。Y-27632的Rho激酶的抑制活性更强,此外,达方吡啶(Dalfampridine),即4-氨基吡啶,是一种广谱的钾通道阻滞剂,用于口服治疗多发性硬化患者以改善他们的行走能力。但是达方吡啶治疗在临床试验中很多不良反应。本文以Y-27632为先导化合物设计合成4-氨基吡啶的衍生物以期得到能明显改善MS患者行走能力并且不良反应较少的4-氨基吡啶类的Rho激酶抑制剂。1.以法舒地尔为先导化合物,以Rho激酶口袋结合模型为指导,设计合成了7个化合物。对化合物进行了EAE体内活性测试。2.研究建立了4-氨基吡啶类Rho激酶抑制剂的合成路线,即以4-氨基吡啶为先导化合物,经亲核取代获得目标产物,通过对4-氨基吡啶上的伯胺的修饰,设计合成了6个化合物。目前对6个化合物做了其在不同浓度对hERG的抑制作用,发现化合物9对hERG具有较好的抑制效果。更多还原

【Abstract】 Multiple sclerosis is a chronic autoimmune disease characterized by the white matter of the central nervous system(CNS)and the infiltration of inflammatory cellsStudies show that Rho kinase has a variety of drug targets Abnormal activation of Rho/Rock has been observed in various disorders of the CNS Furthermore,the dysregulation of ROCK activity is important in the pathogenesis of many neurological diseases,inhibition of Rho kinase can regulate immune,anti-inflammatory,promoting neurite outgrowth and neural stem cell proliferation differentiation and restore the function of damaged nerve As the only listed Rho kinase inhibitor,Fasudil has a definite therapeutic effect on MS Therefore,we take Rho kinase as the target,designed and synthesized a series of Rho kinase inhibitors with isoquinoline scaffold for the treatment of MS Compared with fasudil,Y-27632 represent stronger inhibition activity to Rho kinase In addition,Dalfampridine,ie 4-aminopyridine,is a potassium channel blocker of broad spectrum,has been found to improve walking in patients with any type of MS However,there are many adverse reactions in clinical trials Therefore,we hope to design and synthesize some Rho kinase inhibitors with 4-aminopyridine scaffold which can significantly improve the walking ability of MS patients and the adverse reactions are less1: Seven ROCK inhibitors were designed and synthezed with Fasudil as the lead compound based on ligand-binding pocket model The compounds were tested for EAE activity in vivo But none of them can relieve clinical symptoms of EAE effectively2 Established routes for the synthesis of Rho kinase inhibitor with 4-aminopyridine scaffold Six compounds were designed and synthesized with 4 aminopyridine as the lead compound,by nucleophilic substitution,by modification of the primary amine in 4-aminopyridine obtained target products At present,the inhibitory effect of 6 compounds on hERG at different concentrations was tested,and it was found that compound 9 had better inhibitory effect on hERG更多还原