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.
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)
出处
《中国新药杂志》
CAS
CSCD
北大核心
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)。
