文献类型：期刊文献

英文题名：Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists

作者：Huang, Huang[2];Yu, Ying[2];Gao, Zhenting[2];Zhang, Yong[3];Li, Chenjing[1];Xu, Xing[1];Jin, Hui[2];Yan, Wenzhong[2];Ma, Ruoqun[2];Zhu, Jin[2];Shen, Xu[1,2];Jiang, Hualiang[1,2];Chen, Lili[1];Li, Jian[2]

机构：[1]Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Zunyi Med Coll, Dept Biochem, Zunyi 563003, Guizhou, Peoples R China

年份：2012

卷号：55

期号：16

起止页码：7037

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000307748800005)】；

基金：We gratefully acknowledge the financial supports from the National Natural Science Foundation of China (grants 20902022, 81173105, 30890044), National S&T Major Project, China (grants 2011ZX09102-005-02, 2009ZX09103-646), the Shanghai Committee of Science and Technology (grant 11DZ2260600), the 111 Project (grant B07023), Foundation of Chinese Academy of Sciences (grant KSCX2-EW-Q3), and the Fundamental Research Funds for the Central Universities.

语种：英文

摘要：LBVS of 12480 in-house compounds, followed by HTRF assay, resulted in one nonsteroidal compound (11) with antagonistic activity against FXR (69.01 +/- 11.75 mu M). On the basis of 11, 26 new derivatives (12a-z) were designed and synthesized accordingly. Five derivatives (12f-g, 12p, 12u, and 12y) showed better antagonistic activities against FXR than compound 11. Remarkably, the most potent derivative, 12u (8.96 +/- 3.62 mu M), showed antagonistic capability approximately 10 times and 8-fold higher than that of the control (GS) and the starting compound 11, respectively. 12u was further confirmed to have high binding affinity with FXR alpha LBD, FXR specificity over six other nuclear receptors, and potent antagonistic activity against FXR in two cell testing platforms. 12u strongly suppressed the regulating effects of CDCA on FXR target genes. The therapeutic potential of 12u was identified by lowering the contents of triglyceride and cholesterol in human hepatoma HepG2 cells and in the cholesterol-fed C57BL/6 mices.