靶向脑内糖原合成激酶-3β的环丙酰胺吡啶类化合物的设计和合成及活性评估  

Design,synthesis and activity evaluation of pyridinylcyclopropanecarboxamides targeting GSK-3βin brains

作　　者：贾建华 杨美仙 邱大川 JIA Jian-hua;YANG Mei-xian;QIU Da-chuan(Department of Radiological Medicine,College of Basic Medical Sciences,Chongqing Medical University,Chongqing 400016,China)

机构地区：[1]重庆医科大学基础医学院放射医学实验室,重庆400016

出　　处：《中国新药杂志》2024年第3期279-284,共6页Chinese Journal of New Drugs

基　　金：国家自然科学基金青年项目(82001869);重庆市教委自然科学青年项目(KJQN202100416)。

摘　　要：目的:合成靶向脑内糖原合成激酶-3β(glycogen synthase kinase-3β,GSK-3β)的环丙酰胺吡啶类衍生物,为开发用于阿尔茨海默病(Alzheimer’s disease,AD)治疗的GSK-3β小分子抑制剂及AD脑正电子发射计算机断层成像(positron emission tomography,PET)的显像剂提供优秀先导化合物。方法:通过Pd催化的Suzuki偶联反应形成环丙酰胺吡啶偶联芳环的靶向GSK-3β目标化合物;通过酶抑制实验测试了化合物对GSK-3β的抑制活性;通过SwissADME预测了化合物穿透血脑屏障(blood-brain barrier,BBB)的能力。结果:目标产物结构经1H-NMR,13C-NMR和HRMS确证;化合物表现出对GSK-3β蛋白中等及较高水平的抑制活性;氟代酰胺类化合物(17,18,19和20)可能会穿过BBB。结论:环丙酰胺吡啶类化合物具有开发成用于AD治疗的GSK-3β抑制剂或转化成PET显像剂的潜力。Objective:A series of pyridinylcyclopropanecarboxamide derivatives were designed and synthesized to screen excellent lead compounds for the development of small-molecule inhibitors of glycogen synthase kinase-3β(CSK-3β)and positron emission computed tomography(PET)imaging agents for Alzheimer's disease(AD).Methods:A Suzuki coupling reaction catalyzed by Pd was applied to produce the target compounds.The inhibitory activity of the compounds against GSK-3βwas evaluated by enzyme inhibition assay.The blood-brain barrier(BBB)permeability was predicted by SwissADME.Results:The structures of compounds were confirmed by'H-NMR,13 C-NMR and HRMS.Fluoro-amide compounds(17~20)indicated high affinities to GSK-3βand feasible BBB permeability.Conclusion:Pyridinylcyclopropanecarboxamide compounds have the potential to be developed as GSK-3βinhibitors and PET probes for the treatment and imaging of AD.

关 键 词：环丙酰胺吡啶类衍生物 合成 生物活性 糖原合成激酶-3β抑制剂 正电子发射计算机断层成像显像剂 

分 类 号：R914.5[医药卫生—药物化学]