异噻唑酮取代的间苯二甲酸衍生物的设计、合成及其抑制β-分泌酶活性  

Design,synthesis and inhibitory activity against β-secretase of isothiazolone substituted isophthalic acid derivatives

作　　者：高善云[1] 顾为[1] 程军平[1] 程肖蕊[1] 周文霞[1] 聂爱华[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《中国药物化学杂志》2010年第6期467-475,共9页Chinese Journal of Medicinal Chemistry

摘　　要：目的发现新结构的β-分泌酶抑制剂。方法基于对β-分泌酶与其典型的抑制剂结合位点的分析,辅以分子对接实验,设计并合成异噻唑酮取代的间苯二间羧酸衍生物;采用时间分辨荧光法(time-resolved fluo-rescence,TRF)检测化合物对β-分泌酶的抑制活性。结果合成了10个异噻唑酮取代的苯二羧酸衍生物,其结构经MS和1H-NMR确证,其纯度经HPLC测定;时间分辨荧光法(TRF)检测结果显示有4个化合物对β-分泌酶具有显著的抑制活性,其中化合物22a抑制β-分泌酶的IC50值为13.7nmo.lL-1。结论发现了新的β-分泌酶抑制剂,得出了初步的构效关系,为进一步的结构优化奠定了基础。Aim To discover new structure of β-secretase inhibitors.Methods Combining with Dock method and basing on the structural feature of active site of β-secretase binding to the typical inhibitors,isothiazolone substituted isophthalic acid derivatives were designed and synthesized.Time-resolved fluorescence（TRF） was used to evaluate the inhibitory activity of these compounds against β-secretase.Results Ten target compounds were synthesized and their structures were identified by MS and 1H-NMR.The purity of these compounds was determined by HPLC.Binding assay（TRF） showed that four of these ten compounds had obvious inhibitory activity against β-secretase.Especially,the IC50 value of compound 22a against β-secretase was 13.7 nmol·L-1.Conclusion New type β-secretase inhibitors were discovered.The preliminary structure-activity relationship concluding from this research will give a direction for the structural optimization of these β-secretase inhibitors.

关 键 词：Β-分泌酶 抑制剂 设计 合成 

分 类 号：R91[医药卫生—药学]