Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: Virtual screening, synthesis, and biological evaluation

被引：26
|
作者：
Deng, Guanghui [1 ]
Li, Weihua [1 ]
Shen, Jianhua [1 ]
Jiang, Hualiang [1 ,2 ]
Chen, Kaixian [1 ]
Liu, Hong [1 ]
机构：
[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Drug Discovery & Design Ctr,Grad Sch, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
[2] E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 20期
基金：
中国国家自然科学基金;
关键词：
farnesoid X receptor; pyrazolidine-3,5-dione; virtual screening;
D O I：
10.1016/j.bmcl.2008.09.027
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The identification of a novel pyrazolidine-3,5-dione based scaffold hit compound as Farnesoid X receptor (FXR) partial or full agonist has been accomplished by means of virtual screening techniques. A series of pyrazolidine-3,5-dione derivatives (1a-u and 7) was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activities against FXR. Most of them showed agonistic potencies and 10 of them (1a, 1b, 1d-f, 1j, 1n, 1t, 5b, and 7) exhibited lower EC(50) values than the reference drug CDCA. Molecular modeling studies for the representative compounds 1a, 1d, 1f, 1j, 1n, 1u, 5b, and 7 were also presented. The novel structural scaffold has provided a new direction for finding potent and selective FXR partial and full agonists (referred to as 'selective bile acid receptor modulators', SBARMs). (c) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5497 / 5502
页数：6
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