新型糖尿病治疗药物(GLP-1R和FFAR1双重激动剂)的分子构建、活性评估及作用机制研究

Glucagon like peptide -1 (GLP-1) has excellent hypoglycemic activity, but it is easy to be degraded in vivo. The GLP-1 analogs in the market are affected by the long side chain that their agonist activity and hypoglycemic activity are reduced to some extent. The free fatty acid receptor 1 (FFAR1) agonist can response to lipid signal, and can be used as the "amplifier" of GLP-1 to promote the release of insulin. At the same time, it can be slowly released as it is closely combined with the serum albumin. The subject aims to get GLP-1R/FFAR1 dual agonists by combining the potent FFAR1 agonists and adjustable GLP-1 analogues with different linkers based on mechanism design. The target compounds will be evaluated on GLP-1R/FFAR1 agonist activity, enzyme resistance, plasma stability and hypoglycemic activity in vivo. To prolong the half-time of GLP-1 derivatives, and improve their hypoglycemic activity, the obtained candidates can be further researched the synergetic mechanisms and metabolism. Ultimately, the information obtained from the structure modification for the hypoglycemic effect and half-life, as well as the exploration of interaction with receptors, will provide us a theoretical basis for the dual receptor agonists to initiate a new area for the treatment of diabetes.

胰高血糖素样肽-1(GLP-1)降糖活性优异，但体内易被降解，半衰期短。已上市的GLP-1 类似物，受长效化侧链影响，其受体激动及降糖活性均不同程度地降低。而游离脂肪酸受体1 (FFAR1)激动剂既能响应脂质信号，作为GLP-1的“信号放大器”，协同促进胰岛素释放，又能与血清白蛋白紧密结合，缓慢释药。本课题利用同一靶细胞上不同信号通路，基于机制设计，将FFAR1强效激动剂以不同连接臂缀合到优选GLP-1的可修饰氨基酸位点上，得到GLP-1R/F FAR1双重激动剂。对目标化合物进行两受体激动活性、酶及血浆稳定性及整体动物降糖活性评估。期望延长GLP-1衍生物作用时间的同时，更大限度地提高其降糖活性，获得可进一步开发的候选药物，继而对优选化合物进行深入的协同增效机制、体内外代谢模式研究，总结其结构变化对疗效和半衰期的影响规律，探索其与受体的作用模式，可望开辟糖尿病药物研究的新领域。

胰高血糖素样肽-1(GLP-1)降糖活性优异，但体内易被降解，半衰期短。已上市的GLP-1类似物，受长效化侧链影响，其受体激动及降糖活性均不同程度地降低。而游离脂肪酸受体1(FFAR1)激动剂既能响应脂质信号，作为GLP-1的“信号放大器”，协同促进胰岛素释放，又能与血清白蛋白紧密结合，缓慢释药。本课题设计并合成了28个小分子FFAR1激动剂，在正常小鼠体内均有较强降血糖效果，最优化合物I-14 可以显著降低2 型糖尿病小鼠血糖值，具有良好的药代动力学性质且无潜在肝毒性风险；随后利用同一靶细胞上不同信号通路，基于机制设计，将FFAR1强效激动剂以不同连接臂缀合到优选GLP-1的可修饰氨基酸位点上，得到GLP-1R/FFAR1双重激动剂。所有缀合物在GLP-1R或GCGR高表达的HEK293细胞上检测对GLP-1R或GCGR的受体激动活性水平，以及进行腹腔糖耐量实验评估降糖活性，单次给药多次给糖腹腔糖耐量实验和2型糖尿病模型不禁食降糖实验评估长效化降糖时间。并对优选缀合物进行2型糖尿病模型小鼠的长期给药治疗实验，DIO模型小鼠食欲抑制实验，SD大鼠的胰岛素释放实验，及DIO模型小鼠的长期给药治疗实验以及ob/ob模型鼠的不禁食降糖实验。其中，缀合物 CY-5具有出色的降糖稳定时间和极好的体重稳定作用，有望进一步开发成为肥胖症和糖尿病的有效治疗药物。