Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

被引：38

作者：

Cai, Wenqing ^{[1
,2
]}

Wu, Jingwei ^{[2
]}

Liu, Wei ^{[2
]}

Xie, Yafei ^{[2
]}

Liu, Yuqiang ^{[2
]}

Zhang, Shuo ^{[3
]}

Xu, Weiren ^{[2
]}

Tang, Lida ^{[2
]}

Wang, Jianwu ^{[1
]}

Zhao, Guilong ^{[2
]}

机构：

[1] Shandong Univ, Sch Chem & Chem Engn, Jinan 250100, Peoples R China

[2] Tianjin Inst Pharmaceut Res, Tianjin Key Lab Mol Design & Drug Discovery, Tianjin 300193, Peoples R China

[3] Shandong Acad Sci, Adv Mat Inst, Shandong Key Lab Special Silicon Containing Mat, Jinan 250014, Shandong, Peoples R China

来源：

MOLECULES | 2018年 / 23卷 / 02期

关键词：

gout; hyperuricemia; URAT1; inhibitor; lesinurad; structure-activity relationship (SAR); synthesis; GOUT; HYPERURICEMIA; DISEASE; BURDEN; IDENTIFICATION; MECHANISMS; EFFICIENT; THERAPIES; HISTORY; DESIGN;

D O I：

10.3390/molecules23020252

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

In order to systematically explore and better understand the structure- activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectiv ely (IC50 = 0.035 mu M against human URAT1 for 1h vs. 7.18 mu M and 0.28 mu M for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

引用

页数：38

共 59 条

[1]

Hyperuricemia, Gout, and Cardiovascular Disease: An Update [J].