首页|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

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

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
  • 维普
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1 H-NMR,13 C-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.
Design,synthesis and activity evaluation of pyridinylcyclopropanecarboxamides targeting GSK-3β in brains
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(GSK-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-3β was evaluated by enzyme inhibition assay.The blood-brain barrier(BBB)permeability was predicted by SwissADME.Results:The structures of compounds were confirmed by 1 H-NMR,13 C-NMR and HRMS.Fluoro-amide compounds(17～20)indicated high affinities to GSK-3β and feasible BBB permeability.Conclusion:Pyridinylcyclopropanecarboxamide compounds have the potential to be developed as GSK-3β inhibitors and PET probes for the treatment and imaging of AD.

pyridinylcyclopropanecarboxamide derivativessynthesisinhibitory activityglycogen synthase kinase-3β inhibitorspositron emission tomography imaging agents

贾建华、杨美仙、邱大川

展开 >

重庆医科大学基础医学院放射医学实验室,重庆 400016

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

国家自然科学基金青年项目重庆市教委自然科学青年项目

82001869KJQN202100416

2024

中国新药杂志
中国医药科技出版社 中国医药集团总公司 中国药学会

中国新药杂志

CSTPCD北大核心
影响因子：1.039
ISSN：1003-3734
年,卷(期)：2024.33(3)
  • 21