PMID- 36107013
OWN - NLM
STAT- MEDLINE
DCOM- 20221014
LR  - 20221207
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 65
IP  - 19
DP  - 2022 Oct 13
TI  - Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor 
      Antagonists to Ameliorate Nonalcoholic Steatohepatitis.
PG  - 13452-13472
LID - 10.1021/acs.jmedchem.2c01394 [doi]
AB  - 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 muM. 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.
FAU - Zhang, Chenlu
AU  - Zhang C
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Liu, Yameng
AU  - Liu Y
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Wang, Ying
AU  - Wang Y
AD  - Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for 
      Drug Discovery, Yantai, Shandong 264117, China.
FAU - Ge, Xiu
AU  - Ge X
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      P.R. China.
FAU - Jiao, Tingying
AU  - Jiao T
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Yin, Jianpeng
AU  - Yin J
AD  - Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for 
      Drug Discovery, Yantai, Shandong 264117, China.
FAU - Wang, Kanglong
AU  - Wang K
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Li, Cuina
AU  - Li C
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Guo, Shimeng
AU  - Guo S
AD  - CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 
      201203, China.
AD  - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 
      210046, China.
FAU - Xie, Xin
AU  - Xie X
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      P.R. China.
AD  - CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 
      201203, China.
AD  - School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 
      210046, China.
AD  - School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced 
      Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
FAU - Xie, Cen
AU  - Xie C
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      P.R. China.
FAU - Nan, Fajun
AU  - Nan F
AUID- ORCID: 0000-0002-2284-3637
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, 
      P.R. China.
AD  - Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for 
      Drug Discovery, Yantai, Shandong 264117, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220915
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Ceramides)
RN  - 0 (Inflammasomes)
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Pentacyclic Triterpenes)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - AE28F7PNPL (Methionine)
RN  - IY9XDZ35W2 (Glucose)
RN  - 4G6A18707N (Betulinic Acid)
SB  - IM
MH  - Animals
MH  - Bile Acids and Salts/pharmacology
MH  - Ceramides
MH  - Fibrosis
MH  - Glucose/metabolism
MH  - Inflammasomes/metabolism
MH  - Inflammation/metabolism
MH  - Islet Amyloid Polypeptide/metabolism
MH  - Liver
MH  - Methionine/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Non-alcoholic Fatty Liver Disease/metabolism
MH  - Pentacyclic Triterpenes
MH  - Receptors, Cytoplasmic and Nuclear/metabolism
MH  - Betulinic Acid
EDAT- 2022/09/16 06:00
MHDA- 2022/10/15 06:00
CRDT- 2022/09/15 10:07
PHST- 2022/09/16 06:00 [pubmed]
PHST- 2022/10/15 06:00 [medline]
PHST- 2022/09/15 10:07 [entrez]
AID - 10.1021/acs.jmedchem.2c01394 [doi]
PST - ppublish
SO  - J Med Chem. 2022 Oct 13;65(19):13452-13472. doi: 10.1021/acs.jmedchem.2c01394. 
      Epub 2022 Sep 15.