Abstract
AbstractFarnesoid X receptor (FXR) plays an important role in regulating glucolipid metabolism, detoxification, and inflammation in liver. Thus, FXR has huge potential on several liver diseases, including drug‐induced liver injury, fibrosis, and fatty liver. In this study, we performed a structure‐based drug design strategy to optimize the previous reported FXR agonist N‐(2‐methoxy‐4‐nitrophenyl)‐2‐((2‐(2‐oxopyrrolidin‐1‐yl)phenyl)amino)acetamide (1). After structure‐based drug design, the optimal compound, 3‐(2‐((2‐(2‐oxopyrrolidin‐1‐yl)phenyl)amino)acetamido)benzoic acid (2, EC50=2.43 μM), was identified by displacing the potentially toxic nitro group of compound 1 with carboxylic acid to obtain new ionic bond with His294. Compound 2 revealed considerable activity on FXR, and exerts best therapeutic effects on alleviating acetaminophen‐induced liver damages in this series by up‐regulation of FXR‐related gene expression in vivo. In summary, these results suggest that compound 2 is a promising FXR agonist suitable for further evaluation.
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