基于GPR119靶点的完全激动剂的设计、合成及其构效关系研究

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.

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。

糖尿病已经成为影响人类健康的重大疾病之一。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，本课题设计了新型的GPR119激动剂以嘧啶并嘧啶环、环戊烯并嘧啶、环己烯并嘧啶和四氢吡啶并嘧啶等多种稠环为母核，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。通过对该系列化合物的合成和体外GPR119激动活性测试及体内口服糖耐量试验，得到2-3个活性良好的化合物，体外激动活性达到纳摩尔级，具有进一步研究价值。该课题进一步完善了GPR119激动剂的构效关系。本课题研究内容共发表论文7篇，其中SCI论文3篇，申请发明专利3篇，培养硕士研究生2名，2019年将有2篇SCI论文发表，超额完成本课题的研究目标。本课题为开发强效的、安全性更高的抗2型糖尿病药物提供科学依据和理论基础。