药学学报, 2019, 54(6): 1069-1074
引用本文:
王永成, 杨亚军, 候现新, 杨颖, 肖志艳. 尿酸盐转运体1抑制剂的设计、合成及活性研究[J]. 药学学报, 2019, 54(6): 1069-1074.
WANG Yong-cheng, YANG Ya-jun, HOU Xian-xin, YANG Ying, XIAO Zhi-yan. Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1)[J]. Acta Pharmaceutica Sinica, 2019, 54(6): 1069-1074.

尿酸盐转运体1抑制剂的设计、合成及活性研究
王永成, 杨亚军, 候现新, 杨颖, 肖志艳
中国医学科学院、北京协和医学院药物研究所, 活性物质发现与适药化研究北京市重点实验室, 北京 100050
摘要:
尿酸盐转运体1(urate transporter 1,URAT1)是抗高尿酸血症的有效靶点。基于目前处于临床Ⅱ期的URAT1抑制剂URC-102的结构,设计合成了14个URC-102类似物,其中4个化合物(9b9c10e10g)显示较强的URAT1抑制活性,化合物9b对URAT1的半数抑制浓度IC50达到0.061 μmol·L-1,显著强于雷西纳德和苯溴马隆。初步的构效关系研究为后续结构优化提供了依据。
关键词:    URAT1抑制剂      高尿酸血症      痛风      URC-102类似物     
Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1)
WANG Yong-cheng, YANG Ya-jun, HOU Xian-xin, YANG Ying, XIAO Zhi-yan
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Urate transporter 1 (URAT1) is a validated target for the treatment of hyperuricemia. Based on the structure of URC-102, which is currently under a phase Ⅱ clinical trial, fourteen novel analogs were designed and synthesized. Among them, four compounds (9b, 9c, 10e and 10g) exhibited substantial inhibitory effect against URAT1. The most active compound 9b showed an IC50 value of 0.061 μmol·L-1, which is significantly more potent than Lesinurad and Benzbromarone. Preliminary SAR was drawn, providing clues for further structural optimization.
Key words:    URAT1 inhibitors    hyperuricemia    gout    URC-102 analogs   
收稿日期: 2019-03-27
DOI: 10.16438/j.0513-4870.2019-0208
基金项目: 国家自然科学基金资助项目(21871295).
通讯作者: 肖志艳
Email: xiaoz@imm.ac.cn
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