FXR antagonist 1

FXR antagonist 1 (compound F6) is an orally active and selective intestinal FXR antagonist (IC50=2.1 μM). FXR antagonist 1 selectively inhibits intestinal FXR signalling through antagonism of intestinal FXR and feedback activation of hepatic FXR to improve hepatic steatosis, inflammation and fibrosis in NASH (nonalcoholic steatohepatitis) models. FXR antagonist 1 can be used in NASH studies.

FXR antagonist 1 (0-100 µM; 24 h) shows FXR antagonistic activities in HEK293T cells^[1].

FXR antagonist 1 (10 mg/kg; p.o.; single daily for 12 weeks) reduces adiposity and improves glucose sensitivity and ameliorates the progress of NASH in GAN-diet-induced NASH mice^[1].
FXR antagonist 1 (10 mg/kg; p.o.; single daily for 12 weeks) inhibits intestinal FXR Signaling but indirectly activates hepatic FXR signaling in GAN-diet-induced mice^[1].
FXR antagonist 1 (3, 10, 30 mg/kg; p.o.; single daily for 4 weeks) dose-dependently alleviates NASH pathologies in HFMCD-diet-induced mice^[1].

References:
[1]. Zhang C, et al. Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis. J Med Chem. 2022 Sep 15.