基于GPR119靶点的完全激动剂的设计、合成及其构效关系研究

项目名称： 基于GPR119靶点的完全激动剂的设计、合成及其构效关系研究

项目编号： No.81460526

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨尊华

作者单位： 江西中医药大学

项目金额： 44万元

中文摘要： 全球2型糖尿病患者的人数已达到一个爆炸性的数字。近年来，G蛋白偶联受体119作为一个新的治疗2型糖尿病药物靶点引起了人们的极大兴趣。GPR119被活化后，导致细胞内cAMP水平升高，刺激血糖依赖性胰岛素分泌和肠肽激素释放。在鼠类动物模型和人体实验中，GPR119激动剂均表现出提高糖耐量和保护胰岛β细胞功能的作用。 基于我们对小分子GPR119激动剂的前期研究结果，本课题设计了以嘧啶并嘧啶环、吡啶并哒嗪、苯并哒嗪、吡啶并吡啶、四氢吡啶并嘧啶和喹啉等多种稠环为中部母核，含有氮杂双环结构为头部和取代芳基为尾部的系列化合物，三部分以氧、氮和硫等原子或单键相连。母核的变化保证了化合物的新颖性和多样性，而刚性的氮杂双环的构型可提高化合物与受体作用的效能，有望得到活性更好的GPR119完全激动剂。通过合成目标化合物和活性筛选，总结构效关系，指导后续化合物设计，以期优化出治疗糖尿病的候选化合物。

中文关键词： 设计与合成；G蛋白偶联受体119；构效关系；完全激动剂

英文摘要： Patients with type 2 diabetes mellitus (T2DM) are reaching an explosive number. GPR119, a class-A G protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, has attracted considerable interest as a T2DM drug target in recent years. The activation of GPR119 increases intracellular cAMP level, leading to enhanced glucose-dependent insulin secretion and incretin release. GPR119 agonists has been shown to improve glucose tolerance and preserve beta cell function in both rodents and humans. Based on our previous study on synthetic GPR119 agonists, series of fused ring system such as pyrimidopyrimidine, pyridopyridazine, benzopyridazine, pyridopyridine, tetrahydropyridopyrimidine and qunoline derivatives are designed bearing azabicycle moiety as the head part and aromatic group as the tail, which were connected by N, O, S atom or single bond directly. Compared with typical GPR119 ligand, variation of the core can keep our compounds novel and diverse, and the rigid azabicycle moiety are expected to show higher efficacy to the receptor to make the compounds to be full agonists. Synthesis of endo/exo and anti/syn isomers of azabicyclic intermediates will be explored. After completion of final compounds synthesis, GPR119 agonist activity will be determined using cells transfected with human GPR119 and cAMP detection kits, and then structure-activity relationship will be studied to guide drug design and optimization to discover antidiabetic candidates.

英文关键词： Design and synthesis;GPR119;structure-activity relationship;full agonists