JMC: A novel strategy for intestinal targeted FXR antagonists in the treatment of NASH

Nonalcoholic steatohepatitis (NASH) is a clinicopathological syndrome
in which lipid accumulation, inflammation, and fibrosis of the liver are externally manifested by multiple risk factors, multiple cell types, and multiple tissues and organs.

On September 15, 2022, Nan Fajun's research group and Xie Cen's research group of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, collaborated to publish an article in the Journal of Medicinal Chemistry entitled "Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate.

FXR and TGR5-mediated bile acid signaling pathways play a key role in the development of glucose and lipid metabolism, inflammation, and liver fibrosis, making them an exciting anti-NASH drug track
。 Nan Fajun's research team has been committed to the development of safe and effective targeting of bile acid receptors of small molecule modulators, based on the similarity between betula acid and bile acid structure, the team proposed the use of C3 hydroxyl inversion for simulating bile acid structure of the basic strategy, successfully found the high fat soluble TGR5 agonist XYT528B (Acta.

FXR, also as a bile acid receptor, has also attracted much attention in the field of metabolic diseases, and recent studies on the improvement of metabolism by activation/antagonism of FXR signaling in different tissues have provided new ideas
for the study of new FXR signaling pathway modulators 。 Different from previous studies on liver FXR, Xie Chen's researchers have found that intestinal FXR can regulate hepatic gluconeogenesis and lipid metabolism across organs, and that specific knockout or antagonistic intestinal FXR signaling can alleviate obesity, diabetes, and fatty liver induced by a high-fat diet (Nat.

Inspired by the endogenous FXR antagonists Gly-MCA and GUDCA, the research team followed the basic strategy of C3-position hydroxyl inversion and obtained a series of highly active and highly selective FXR antagonists
through systematic structure-activity relationship research 。 Among them, the representative compound F6 can selectively target the intestine, significantly alleviating the NASH phenotype induced by the high-fat high-fructose high-cholesterol diet (GAN-diet) and methionine and choline-deficient high-fat diet (HFMCD-diet), and the efficacy of the high-dose group (30 mg/kg) of the HFMCD model is better than that of the clinical drug Aubecholic acid (30 mg/kg).

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(Contributed by Nan Fajun Research Group, Xie Cen Research Group)