糖尿病神经性疼痛(DNP)是糖尿病最常见的慢性并发症之一，目前尚无针对其发病机制的药物上市。游离脂肪酸受体1（FFAR1）是糖尿病领域热门靶标，激活胰岛中的FFAR1能以血糖依赖性方式促进胰岛素分泌，而激活脑组织中FFAR1则能以多元化的机制调控疼痛系统。该项目利用FFAR1在不同靶部位中的不同生理功能，针对DNP患者降糖和镇痛两大临床需求，设计兼具降糖和镇痛作用的新型双效DNP药物。基于前期研究中意外发现的兼备降糖及镇痛双效FFAR1激动剂1，本项目将以改善其活性及血脑屏障通透性为导向，结合计算机辅助药物设计手段，研究其构效关系及构性关系。对优选化合物分别进行降糖及镇痛活性评估、低血糖风险及体内外药效机制研究，期望获得降糖及镇痛活性俱佳的候选化合物。继而对其进行深入的靶点特异性及成瘾性、体内代谢模式、长期有效性及安全性评估，为新型双效DNP药物研制提供理论依据和有自主知识产权的候选药物。

Diabetic neuropathic pain (DNP) is one of the most common chronic complications of diabetes, and there is no available drug for its pathogenesis. Free fatty acid receptor 1 (FFAR1) is an attractive target in the field of diabetes. Activation of FFAR1 in pancreatic β-cells promotes insulin secretion in a glucose-dependent manner, while activation of FFAR1 in brain tissue regulates the pain system by a diverse set of mechanisms. Based on the different physiological functions of FFAR1 in different tissue, a novel dual-effect DNP drug with hypoglycemic and analgesic effects was designed to meet the clinical needs of glycemic control and analgesia in patients with DNP. Based on our previously researched FFAR1 agonists with hypoglycemic and analgesic effects, this research will be guided to improve its activity and permeability of the blood-brain barrier. Moreover, the computer-assisted drug design strategy will also be used to systematically explore its structure-activity relationship and structure-property relationship. To obtain candidates with good hypoglycemic and analgesic activities, the target compounds were evaluated for hypoglycemic and analgesic activity, hypoglycemic risk and pharmacodynamic mechanism both in vitro and in vivo. The obtained candidates were further investigated for their target specificity and addiction, metabolism pathway in vivo, long-term efficacy and safety. All of these results will promoted the understanding of theoretical basis and provided new dual-effect DNP candidates with independent intellectual property rights.