含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂的合成及其构效关系  

Synthesis and The Structure-activity Relationship(SAR) of Naphthyltriazolylmethane-based Thioacetic Acids as Uric Acid Transporter 1(URAT1) Inhibitors

作　　者：辛晓[1,2] 刘巍[2] 谢亚非[2] 刘长鹰[2] 汤立达[2] 徐为人[1,2] 赵桂龙[2] XIN Xiao LIU Wei XIE Ya-fei LIU Chang-ying TANG Li-da ZHAO Gui-long(Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China)

机构地区：[1]天津中医药大学研究生院,天津300193 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300193

出　　处：《合成化学》2017年第6期461-474,共14页Chinese Journal of Synthetic Chemistry

基　　金：天津市科技支撑计划重点资助项目(16YFZCSY00910)

摘　　要：分别以1-溴萘和酮或1-萘甲醛及有机金属试剂为原料,经12步反应合成了8个含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂(1h^1o),其结构经~1H NMR,^(13)C NMR和MS(ESI)表征。体外活性测试结果显示:对URAT1的抑制活性最强的是1k,是阳性对照药lesinurad的133倍[IC_(50)=0.054μmol·L^(-1)(1k),7.18μmol·L^(-1)(lesinurad)]。Eight naphthyhriazolylmethane-based thioacetic acids （1h -1o） were synthesized as uric acid transporter 1 （URAT1） inhibitors by 12 steps using 1-bromonaphthalene and ketones or 1-naphth- aldehyde and alkyl organometallic reagents as starting materials. The structures were characterized by 1H NMR, 13C NMR and MS（ESI）. In vitro URAT1 inhibitory assay showed that lk was the most.po- tent URAT1 inhibitor among target compounds, which was 133-fold more potent than positive control lesinurad（ IC50 =0.054 μmol·L^-1 for lk against human URAT1 vs 7.18 μmol·L^-1 for lesinurad）.

关 键 词：1-溴萘 1-萘甲醛 痛风 高尿酸血症 尿酸转运体1(URAT1) 合成 lesinurad 构效关系 

分 类 号：O623.626[理学—有机化学] O621.3[理学—化学]