Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy
文献类型：期刊论文
| 作者 | Wang, Xiao-yin; Zhang, Shu-yong; Li, Jing ; Liu, Hua-nan; Xie, Xin; Nan, Fa-jun
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2014-11 |
| 卷号 | 35期号:11页码:1463-1472 |
| 关键词 | TGR5 activator betulinic acid derivatives GLP-1 lipophilic structure modifications |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2014.97 |
| 文献子类 | Article |
| 英文摘要 | Aim: TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1 (GLP-1) secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betulinic acid. Methods: A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. Results: Biological data revealed that the 3-alpha-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-beta-OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-alpha betulinic derivatives and enhanced the activity differences between 3-alpha and 3-beta derivatives. The 3-alpha-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. Conclusion: This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists. |
| WOS关键词 | BILE-ACIDS ; BETULINIC ACID ; NUCLEAR RECEPTOR ; IDENTIFICATION ; ACTIVATION ; AGENT |
| 资助项目 | National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09304011] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2013ZX09507001] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09301001-005] ; National Basic Research Program of China (973 Program)[2014CB541906] ; National Natural Science Foundation of China[30725049] ; National Natural Science Foundation of China[81202341] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5282171 |
| WOS记录号 | WOS:000344991100013 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276850]  |
| 专题 | 国家新药筛选中心 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 | Xie, Xin |
| 作者单位 | Chinese Acad Sci, State Key Lab Drug Res, CAS Key Lab Receptor Res, Natl Ctr Drug Screening,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Xiao-yin,Zhang, Shu-yong,Li, Jing,et al. Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy[J]. ACTA PHARMACOLOGICA SINICA,2014,35(11):1463-1472. |
| APA | Wang, Xiao-yin,Zhang, Shu-yong,Li, Jing,Liu, Hua-nan,Xie, Xin,&Nan, Fa-jun.(2014).Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy.ACTA PHARMACOLOGICA SINICA,35(11),1463-1472. |
| MLA | Wang, Xiao-yin,et al."Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy".ACTA PHARMACOLOGICA SINICA 35.11(2014):1463-1472. |
入库方式： OAI收割
来源：上海药物研究所
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