Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal FarnesoidX Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism

doi:10.1002/cmdc.201500136

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 生物技术药物研发中心（筹）

	Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal FarnesoidX Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
	Huang, Huang 1; Si, Pei 3; Wang, Lei 1; Xu, Yong 2; Xu, Xin 3; Zhu, Jin 1; Jiang, Hualiang1,3 ; Li, Weihua 1; Chen, Lili3 ; Li, Jian 1
刊名	CHEMMEDCHEM
	2015-07
卷号	10 期号:7 页码:1184-1199
关键词	antagonists mechanism of action molecular dynamics nonsteroidal ligands receptors
ISSN号	1860-7179
DOI	10.1002/cmdc.201500136
文献子类	Article
英文摘要	FarnesoidX receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2 +/- 0.2M). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR.
资助项目	National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[21372001] ; National Natural Science Foundation of China[91313303] ; National Natural Science Foundation of China[81173105] ; National Natural Science Foundation of China[81373462] ; Program for New Century Excellent Talents in University[NCET-12-0853] ; "Shu Guang" project - Shanghai Municipal Education Commission[14SG28] ; "Shu Guang" project - Shanghai Education Development Foundation[14SG28] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	BILE-ACID RECEPTOR ; SALT EXPORT PUMP ; ORPHAN NUCLEAR RECEPTOR ; X-RECEPTOR ; MEDICINAL CHEMISTRY ; NATURAL PRODUCT ; BINDING DOMAIN ; IDENTIFICATION ; POTENT ; CHOLESTEROL
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-V C H VERLAG GMBH
WOS记录号	WOS:000357030200008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276484]
专题	生物技术药物研发中心（筹）药物发现与设计中心
通讯作者	Huang, Huang
作者单位	1.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 2.Humanwell Healthcare Grp Co Ltd, Wuhan 430075, Hubei, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Huang, Huang,Si, Pei,Wang, Lei,et al. Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal FarnesoidX Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism[J]. CHEMMEDCHEM,2015,10(7):1184-1199.
APA	Huang, Huang.,Si, Pei.,Wang, Lei.,Xu, Yong.,Xu, Xin.,...&Li, Jian.(2015).Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal FarnesoidX Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism.CHEMMEDCHEM,10(7),1184-1199.
MLA	Huang, Huang,et al."Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal FarnesoidX Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism".CHEMMEDCHEM 10.7(2015):1184-1199.