新型抗糖尿病药物靶标FABP4及其小分子抑制剂药理机制研究

项目名称： 新型抗糖尿病药物靶标FABP4及其小分子抑制剂药理机制研究

项目编号： No.81473262

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王贺瑶

作者单位： 中国科学院上海药物研究所

项目金额： 80万元

中文摘要： 2型糖尿病的发生发展与脂质代谢异常及外周组织非感染性炎症反应关系密切。脂肪细胞型脂肪酸结合蛋白（FABP4）近年来被证实与肥胖2型糖尿病密切相关，在脂质代谢及炎症反应中起极其重要作用。FABP4基因缺陷可减轻高脂诱导糖尿病小鼠症状，血清FABP4水平较低的个体患2型糖尿病的机率降低。FABP4抑制剂已成为新型抗糖尿病药物研发热点。我们发现了一类新型具有自主知识产权的FABP4小分子抑制剂，其中化合物I-10与已报道的FABP4抑制剂相较有其独特优势，其对FABP4具有良好的抑制作用及选择性，能有效降低db/db 2型糖尿病小鼠血糖，减轻外周组织胰岛素抵抗及炎症。本项目拟在多种体外细胞模型及糖尿病动物模型中评价化合物I-10降糖药效机制，评估其成药性。同时结合体内外基因干扰及过表达技术，深入研究FABP4在糖尿病发生发展过程中的作用，为FABP4作为抗糖尿病靶标的有效性和安全性提供依据。

中文关键词： 2型糖尿病；FABP4；小分子抑制剂；药理机制

英文摘要： The development of type 2 diabetes is highly associated with abnormal lipids metabolism and non-infectious inflammatory in peripheral tissues. Recently, the adipocyte fatty acid binding protein (FABP4) has been proven to contribute to obesity related type 2 diabetes and plays a key role in lipid metabolism and inflammatory response. Deficiency of FABP4 genes could improve high fatty food-induced diabetes in rodents. Clinical studies also confirmed that there could be reduced risk of diabetes in persons whom have lower serum FABP4 level. Therefore, research on FABP4 inhibitors has become hotspot in development of anti-diabetic drugs. We discovered novel FABP4 inhibitors with proprietary intellectual property rights via in vitro screening. One of the small molecule inhibitor, I-10, could inhibit FABP4 with high efficiency and specificity. It could decrease blood glucose in type 2 diabetic db/db mice, insulin resistance and inflammatory in peripheral tissues. In this study, the pharmacological mechanism of the anti-diabetic effect of I-10 would be further investigated in multiple in vitro and in vivo models, and the druggability of I-10 would be also evaluated. Meanwhile, gene interference and overexpression technology would be used to study the role of FABP4 in the development of type 2 diabetes. This study would provide novel evidences to increase the validity and safety of FABP4 as a drug target in the treatment of diabetes.

英文关键词： Type 2 diabetes;FABP4;small molecule inhibitor;pharmacological mechanism