胰高血糖素样肽-1(GLP-1)作为一种肠促胰岛素，是治疗2型糖尿病的重要靶标。促进GLP-1生成和抑制DPP-IV活性均是有效发挥GLP-1活性的重要途径。.本课题运用一药多靶的药物设计策略，利用GPR119激动剂和DPP-IV抑制剂作用于同一通路的特点，基于GLP-1的生物学效应，通过药效片段“融合”的方式，开展了同时靶向GPR119和DPP-IV的化合物设计、合成及降糖活性研究。以前期获得的具有较强GPR119激动作用和DPP-IV抑制活性的化合物HBK001为先导物，分阶段分层次开展药物分子设计，重点针对HBK001药代性质和潜在毒性问题，对末端疏水侧链、哌嗪连接链以及黄嘌呤母核进行结构修饰和改造，希望通过循环设计-合成-评价-设计的方式，总结和完善构效关系规律。同时找到结构-药代和结构-毒性之间的关系规律，最终获得抗糖尿病活性强、代谢性质优良并且毒副作用低的先导物或候选物。

Glucagon-like peptide-1 (GLP-1), an incretin hormone, has been emerged as a new therapeutic target for T2DM. Increasing the release of GLP-1 or inhibiting the activity of DPP-IV are both effective approaches for GLP-1-based T2DM treatment..Based on the synergistic effects of DPP-IV inhibition and GPR119 agonism in GLP-1 pathway, the compounds with dual modulation effect targeting GPR119 and DPP-IV were designed, synthesized and evaluated for the treatment of T2DM through the “merged” pharmacophore strategy. The lead compound HBK001 with good GPR119 agonism and potent selective DPP-IV inhibition activities was discovered in our previous work. In order to improve the pharmacokinetics profile and reduce the toxicity of the lead compound HBK001, further molecular design and SAR research will be developed by the structure modification of ending hydrophobic side chain, piperazine linker and xanthine scaffold through the re-cycle design-synthesis- evaluation-design protocol. Meanwhile, the structure-pharmacokinetics and structure-toxicity relationship will also be concluded. The aim is to obtain the novel lead compound or drug candidate with high anti-diabetic activity, low toxicity and good pharmacokinetics property for further pre-clinical investigation.