中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis

文献类型：期刊论文

作者Li, Junyou1,2; Liu, Mengqi1,2; Li, Yazhou1,3; Sun, Dan-dan1; Shu, Zhihao1; Tan, Qian1; Guo, Shimeng1,3; Xie, Rongrong1; Gao, Lixin1; Ru, Hongbo1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-11-12
卷号63期号:21页码:12748-12772
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c01065
通讯作者Li, Jia(jli@simm.ac.cn) ; Zhou, Yu(zhouyu@simm.ac.cn)
英文摘要Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.
资助项目National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09201001-003-001] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2019ZX09201001003-010] ; National Natural Science Foundation of China[81673489] ; National Natural Science Foundation of China[21672232] ; National Science Fund for Distinguished Young Scholars[81125023] ; Shanghai Science and Technology Development Funds[19JC1416300] ; Shanghai Science and Technology Development Funds[19YF1457500] ; Shanghai Science and Technology Development Funds[19431901000] ; K. C. Wong Education Foundation
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000592734300031
源URL[http://119.78.100.183/handle/2S10ELR8/296455]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Zhou, Yu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
4.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Peoples R China
推荐引用方式
GB/T 7714		 Li, Junyou,Liu, Mengqi,Li, Yazhou,et al. Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(21):12748-12772.
APA Li, Junyou.,Liu, Mengqi.,Li, Yazhou.,Sun, Dan-dan.,Shu, Zhihao.,...&Zhou, Yu.(2020).Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis.JOURNAL OF MEDICINAL CHEMISTRY,63(21),12748-12772.
MLA Li, Junyou,et al."Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis".JOURNAL OF MEDICINAL CHEMISTRY 63.21(2020):12748-12772.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。