基于二肽基肽酶4(DPP-4)靶点设计的五种降糖活性杂环合成及构效关系研究进展  

Research Progress on the Synthesis and Structure-Activity Relationship of Five Hypoglycemic Active Heterocycles Based on Dipeptidyl Peptidase 4(DPP-4)Target Design

作　　者：孔媛芳 杨彬 庄严 张京玉[1] 孙德梅[1] 董春红 Kong Yuanfang;Yang Bin;Zhuang Yan;Zhang Jingyu;Sun Demei;Dong Chunhong(College of Pharmacy,Henan University of Chinese Medicine,Zhengzhou 450046;Academy of Chinese Medical Science,Henan University of Chinese Medicine,Zhengzhou 450046)

机构地区：[1]河南中医药大学药学院,郑州450046 [2]河南中医药大学中医药科学院,郑州450046

出　　处：《有机化学》2022年第3期770-784,共15页Chinese Journal of Organic Chemistry

基　　金：河南中医药大学仲景高层次人才专项基金(No.00104311-2021-1-8);河南省高等学校重点科研项目(No.20A350004);河南省自然科学基金(No.202300410264)资助项目.

摘　　要：糖尿病是我国慢性疾病中威胁人类健康的主要疾病,治疗糖尿病的药物作用靶点主要有二肽基肽酶4(DPP-4)、单磷酸腺苷活化蛋白激酶(AMPK)、过氧化物酶体增殖物激活受体γ(PPARγ)受体等,其中以DPP-4为靶点的靶向药物研究是近几年的热点.DPP-4抑制剂是治疗2型糖尿病的药物,其最大的优点是不易诱发低血糖和增加体重.据报道,目前已上市的DPP-4靶向药物可引起胰腺炎和超敏等不良反应,因此继续开发新型DPP-4抑制剂的降糖药物,以避免不良反应发生值得进一步深入研究.在系统的文献调研基础上,总结出具有潜在的降糖活性杂环结构,并通过计算机分子模拟对接,针对DPP-4靶点,最终筛选出5种易合成且降糖活性较高的杂环结构,并对其合成路线及构效关系进行归纳总结分析,为今后开发安全高效、结构新颖的DPP-4抑制剂的降糖药物提供研究基础.Recently,diabetes has gradually become a main life-threatening disease in China.Drug targets for the treatment of diabetes mainly include dipeptidyl peptidase 4(DPP-4),adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptor gamma(PPARγ)receptor and so on,in which targeted drug research targeting DPP-4 is a hot spot in recent years.DPP-4 inhibitor is a drug for the treatment of type 2 diabetes,and its biggest advantage is that it is not easy to induce hypoglycemia and increase weight.It is reported that the currently available DPP-4 targeted drugs can cause adverse reactions,such as pancreatitis and hypersensitivity.Therefore,it is worth further studying to continue to develop new hypoglycemic drugs for DPP-4 inhibitors to avoid adverse reactions.According to the systematic literature review,the potential heterocyclic structures with hypoglycemic activity are summarized and through computer molecular simulation docking,five kinds of heterocyclic structures with high hypoglycemic activity and easy synthesis are finally screened out based on DPP-4 target design.The synthesis routes and structure-activity relationships are summarized and analyzed,which provides a research basis for the development of safe,efficient and novel hypoglycemic drugs for DPP-4 inhibitors in the future.

关 键 词：糖尿病 二肽基肽酶4(DPP-4)抑制剂 分子对接 合成方法 构效关系 

分 类 号：TQ460.1[化学工程—制药化工]