二肽基肽酶-IV（DPP-IV）抑制剂安全性良好并具有胰岛细胞的保护功能，符合2型糖尿病的慢性疾病进展特点而适合于长期服用。然而目前DPP-IV抑制剂类药物需每日服用，仍然面临着因患者服药依从性不高而导致的血糖控制不良，使机体遭受不可逆的损伤。因此，开发一周服用一次的长效DPP-IV抑制剂在抗糖尿病新药研究中具有重要意义。本项目拟在我们前期报道的高活性化合物1（IC50= 0.3 nM）的基础上，继续开展对噻吩并嘧啶酮类DPP-IV抑制剂的结构优化，通过同时提升化合物的血浆半衰期和药物-靶标驻留时间来延长其有效作用时间，有望确立新型一周口服一次的长效DPP-IV抑制剂，并探索DPP-IV抑制剂长效化的有效方法，进一步为小分子长效抗糖尿病药物的研发提供科学依据。

Dipeptidyl peptidase-IV （DPP-IV）is a reliable target for anti-diabetic drug discovery. Superior safety and protective function for islet cells of DPP-IV inhibitors conform to the chronic progress features of type 2 diabetes, which make it suitable for long term use. However, current DPP-IV inhibitor drugs are needed to be administered daily, still confronting failed glycemic control due to the poor adherence and causing irreversible damage to the body. Thus, development of well-tolerated oral DPP-IV inhibitors which could be administered once-weekly is meaningful for anti-diabetic drug discovery. This study will go on conducting a structural optimization on our previously reported compound 1, which is a highly potent DPP-IV inhibitor bearing thienopyrimidone scaffold (IC50= 0.3 nM). Through the increase of plasma half life and drug-target residence time, we intend to prolong the therapeutic duration of compounds and identify novel once-weekly DPP-IV inhibitors, in order to provide the feasible approaches and further scientific evidence for long-acting anti-diabetic drug discovery.

一周一次的长效DPP-IV抑制剂在提高服药依从性，维持血糖平稳方面具有明显优势。在前期高活性噻吩并嘧啶酮化合物1（IC50= 0.3 nM）的基础上，我们同时基于药物-靶标结合动力学及药物代谢动力学的理论，对嘧啶酮类化合物开展了药物-靶标解离速率（koff）和药物代谢动力学参数的优化过程。期间，我们设计合成并筛选优化了两个系列近百个化合物，初步证明了嘧啶酮类化合物与其靶标蛋白DPP-IV之间不存在足以支持长效作用的解离速率。另一方面，有步骤的药物代谢动力学性质优化过程则得到了3个化合物，在大鼠体内药效与上市周效药物曲格列汀相当。通过本研究，我们观察到高活性与优良的药物代谢动力学性质对嘧啶酮类DPP-IV抑制剂的长效作用有一定贡献，这为后续DPP-IV抑制剂的快速长效化提供了结构优化的思路。同时，研究过程中我们也注意到若干短半衰期的化合物表现出长效的特点，这也为我们目前展开活性代谢产物研究，继续挖掘DPP-IV抑制剂的其他长效机制提供了研究基础。