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

  • J Med Chem. 2022 Oct 13;65(19):13452-13472. doi: 10.1021/acs.jmedchem.2c01394.
Chenlu Zhang  1 ,  Yameng Liu  1 ,  Ying Wang  2 ,  Xiu Ge  1  3 ,  Tingying Jiao  1 ,  Jianpeng Yin  2 ,  Kanglong Wang  1 ,  Cuina Li  1 ,  Shimeng Guo  4  5 ,  Xin Xie  3  4  5  6 ,  Cen Xie  1  3 ,  Fajun Nan  1  3  2
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. Drug Discovery Shandong Laboratory, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P.R. China.
  • 4. CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 6. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 36107013 DOI: 10.1021/acs.jmedchem.2c01394
Abstract

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 IC50 at 2.1 μM. 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.

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