取代吡唑酮类AMPK直接激活剂的设计合成、构效关系及抗糖尿病药理作用研究

项目名称： 取代吡唑酮类AMPK直接激活剂的设计合成、构效关系及抗糖尿病药理作用研究

项目编号： No.81502910

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张梅

作者单位： 中国科学院上海药物研究所

项目金额： 17.9万元

中文摘要： AMPK是细胞和整体能量代谢的监控器，已经成为抗糖尿病以及心血管疾病的潜力新靶点。目前发现许多用于治疗II 型糖尿病的药物能够通过间接激活AMPK 发挥治疗效应，但可能会存在于AMPK活性不相关的副作用，因此寻找和发现AMPK 的直接激活剂，将是治疗II 型糖尿病的一个有效途径。本项目团队在前期工作中发现小分子化合物ZLN006 能够有效地激活AMPK，经进一步结构优化，发现化合物ZM582m能在分子水平以较大的激活倍数激活AMPK，并在多种细胞系中增加AMPK和ACC磷酸化。本项目拟在AMPK直接激动剂ZM582m基础上，在多个位点进行系列结构修饰和优化，并结合成药性研究，以期发现在分子和细胞水平均能有效直接激活AMPK且代谢稳定，动物水平有效改善糖尿病db/db小鼠糖脂代谢紊乱，1-2个具有进一步开发价值新型抗糖尿病药物先导化合物。

中文关键词： 糖尿病；单磷酸腺苷激活的蛋白激酶；构效关系；直接激活剂；先导化合物

英文摘要： AMP-activated protein kinase (AMPK) is the major sensor of cellar energy and master regulator of metabolic homeostasis. It is an attractive therapeutic target for type 2 diabetes and metabolic syndrome.Recent discoveries proved many medicines exerted their anti-diabetic effects at least partly through indirect AMPK activation. So the discovery of small-molecule activators of AMPK, especially direct activators, will be a potential method for therapy of type II diabetes..During the small-scale direct AMPK agonist screening, a small-molecule compound ZLN006 was found. ZLN006 can effectively activate AMPK on molecular and cellular level. Via analyzing ZLN006’s structure and structural optimization, we found compound ZM582m has more potent efficient. In this application, we aim to design and synthesize of new small molecule compound libraries in order to improve the activity and the metabolic stability of the compounds from compound ZM582m. And through extensive SAR studies to discover compounds, which could effectively direct activation of AMPK, do not affect the mitochondrial membrane potential, possess metabolic stability and efficacy on diet induced obesity mouse model and finally to provide the AMPK agonist as lead compound toward type 2 diabetes.

英文关键词： diabetes mellitus;AMPK;SAR;direct activators;lead compound