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Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis

文献类型：期刊论文

作者Zhang, Chenlu6; Liu, Yameng6; Wang, Ying4; Ge, Xie; Jiao, Tingying6; Yin, Jianpeng4; Wang, Kanglong6; Li, Cuina6; Guo, Shimeng2,3; Xie, Xin1,2,5,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-09-15
页码21
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01394
通讯作者Xie, Cen(xiecen@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn)
英文摘要Farnesoid X receptor (FXR) has emerged as a promising therapeutic target for nonalcoholic steatohepatitis (NASH) because of its tightly interwoven relationship with bile acid homeostasis, inflammation, fibrosis, and glucose and lipid metabolism. Evidence showed that intestinal FXR antagonism exhibited remarkable metabolic improvements in mice. Herein, we developed a series of betulinic acid derivatives as potent intestinal FXR antagonists, and F6 was identified as the most potent one with an IC(50 )at 2.1 mu M. F6 selectively inhibited intestinal FXR signaling and ameliorated the hepatic steatosis, inflammation, and fibrosis in Gubra-amylin NASH (GAN) and high-fat with methionine and choline deficiency (HFMCD) diet-induced NASH models. The beneficial effects were achieved by direct antagonism of intestinal FXR and feedback activation of hepatic FXR, thereby decreasing ceramides and repressing inflammasome activation in the liver. Collectively, our work substantially supports F6 as a promising drug candidate against NASH and demonstrates that antagonism of intestinal FXR signaling is a practical strategy for treating metabolic diseases.
WOS关键词NLRP3 INFLAMMASOME ; NUCLEAR RECEPTOR ; SIGNALING AXIS ; FXR AGONIST ; BILE-ACIDS ; CHEMOTYPE
资助项目National Natural Science Foundation of China[82003572] ; National Natural Science Foundation of China[91957116] ; National Natural Science Foundation of China[82030109] ; National Natural Science Foundation of China[82104261] ; Shanghai Municipal Science and Technology Major Project ; Shanghai Rising-Star Program[20QA1411200]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000859286800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/302667]  
专题新药研究国家重点实验室
通讯作者Xie, Cen; Nan, Fajun
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Drug Discovery Shandong Lab, Yantai 264117, Shandong, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Chenlu,Liu, Yameng,Wang, Ying,et al. Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:21.
APA Zhang, Chenlu.,Liu, Yameng.,Wang, Ying.,Ge, Xie.,Jiao, Tingying.,...&Nan, Fajun.(2022).Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis.JOURNAL OF MEDICINAL CHEMISTRY,21.
MLA Zhang, Chenlu,et al."Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis".JOURNAL OF MEDICINAL CHEMISTRY (2022):21.

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来源：上海药物研究所

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