Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal FarnesoidX Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
文献类型：期刊论文
| 作者 | Huang, Huang1; Si, Pei3; Wang, Lei1; Xu, Yong2; Xu, Xin3; Zhu, Jin1; Jiang, Hualiang1,3 ; Li, Weihua1; Chen, Lili3; Li, Jian1
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| 刊名 | CHEMMEDCHEM
 |
| 出版日期 | 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. |
| WOS关键词 | BILE-ACID RECEPTOR ; SALT EXPORT PUMP ; ORPHAN NUCLEAR RECEPTOR ; X-RECEPTOR ; MEDICINAL CHEMISTRY ; NATURAL PRODUCT ; BINDING DOMAIN ; IDENTIFICATION ; POTENT ; CHOLESTEROL |
| 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研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000357030200008 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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