摘要
目的以尿酸转运体1(URAT1)抑制剂verinurad为结构模板,研究吡啶-4-丙酸类URAT1抑制剂的构效关系。方法以3-溴吡啶和芳基硼酸为主要起始原料合成目标化合物(主要步骤为Suzuki偶合反应),测试目标化合物在体外对URAT1的抑制活性(IC50)。结果合成了24个吡啶-4-丙酸类URAT1抑制剂,体外活性测试结果显示绝大部分目标化合物对URAT1有较强的抑制作用(IC50在0.1~10μmol·L^(-1)之间,活性最强的8v的IC50值为0.24μmol·L^(-1)),但是均弱于verinurad。结论目标化合物的构效关系研究表明verinurad分子中的S原子对维持其URAT1抑制活性是不可或缺的。
Twenty four pyridine-4-propionic acid derivatives of urate transporter 1（URAT1） inhibitor verinurad were designed and synthesized starting from 3-bromopyridine and arylboronic acids,with Suzuki coupling as the key step.The synthesized compounds were evaluated by in vitro URAT1 inhibitory assay.The preliminary results showed that most of the synthesized compounds exhibited strong inhibitory activity against URAT1 with IC50 of 0.1-10 μmol·L^-1.The most active compound 8v（IC50= 0.24 μmol·L^-1against URAT1） which was 30-fold more active than lesinurad（IC50= 7.18 μmol·L^-1against URAT1）,was still 7.5-fold less active than verinurad（IC50= 0.032 μmol·L^-1against URAT1）.The structure-activity relationship strongly indicated that the sulfur atom in verinurad was indispensable for its URAT1 inhibitory activity.
作者
辛晓
刘钰强
李川
商倩
周植星
谢亚非
汤立达
刘长鹰
徐为人
赵桂龙
XIN Xiao LIU Yu-qiang LI Chuan SHANG Qian ZHOU Zhi-xing XIE Ya-fei TANG Li-da LIU Chang-ying XU Wei-ren ZHAO Gui-long(Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China Tianfin Key Laboratory of Molecular Design and Drug Discovery, Tianfin Institute of Pharmaceutical Research, Tianjin 300193, China)
出处
《中国药物化学杂志》
CAS
CSCD
2016年第6期437-448,共12页
Chinese Journal of Medicinal Chemistry
基金
天津市科技支撑计划重点项目(16YFZCSY00910)
