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

doi:10.1021/jm3002718

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	Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists
	Huang, Huang 3; Yu, Ying 3; Gao, Zhenting 3; Zhang, Yong 2; Li, Chenjing 1; Xu, Xing 1; Jin, Hui 3; Yan, Wenzhong 3; Ma, Ruoqun 3; Zhu, Jin 3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2012-08-23
卷号	55 期号:16 页码:7037-7053
ISSN号	0022-2623
DOI	10.1021/jm3002718
文献子类	Article
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.
资助项目	National Natural Science Foundation of China[20902022] ; National Natural Science Foundation of China[81173105] ; National Natural Science Foundation of China[30890044] ; National S&T Major Project, China[2011ZX09102-005-02] ; National S&T Major Project, China[2009ZX09103-646] ; Shanghai Committee of Science and Technology[11DZ2260600] ; 111 Project[B07023] ; Fundamental Research Funds for the Central Universities[00000000] ; Foundation of Chinese Academy of Sciences[KSCX2-EW-Q3]
WOS关键词	BILE-ACID RECEPTOR ; ORPHAN NUCLEAR RECEPTOR ; SALT EXPORT PUMP ; METABOLIC-DISORDERS ; LIVER ; CHOLESTEROL ; IDENTIFICATION ; EXPRESSION ; AGONISTS ; DISEASE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000307748800005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277984]
专题	生物技术药物研发中心（筹）中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Chen, Lili
作者单位	1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Zunyi Med Coll, Dept Biochem, Zunyi 563003, Guizhou, Peoples R China 3.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;
推荐引用方式 GB/T 7714	Huang, Huang,Yu, Ying,Gao, Zhenting,et al. Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(16):7037-7053.
APA	Huang, Huang.,Yu, Ying.,Gao, Zhenting.,Zhang, Yong.,Li, Chenjing.,...&Li, Jian.(2012).Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists.JOURNAL OF MEDICINAL CHEMISTRY,55(16),7037-7053.
MLA	Huang, Huang,et al."Discovery and Optimization of 1,3,4-Trisubstituted-pyrazolone Derivatives as Novel, Potent, and Nonsteroidal Farnesoid X Receptor (FXR) Selective Antagonists".JOURNAL OF MEDICINAL CHEMISTRY 55.16(2012):7037-7053.