FXR agonist 17

FXR agonist17 is an orally active, steroidal FXR agonist with EC50 values of 42.2 nM (TR-FRET) and 176.4 nM (luciferase reporter assay). It can activate TGR5 (EC50 = 2.6 μM) but does not activate hMRGPRX4. FXR agonist17 exhibits anti-inflammatory, hepatoprotective, and antifibrotic effects, improving the activity score of metabolic dysfunction-associated fatty liver disease (NAFLD) and reducing the severity of liver fibrosis. This compound is applicable for research in NAFLD, cholestatic liver diseases, and liver fibrosis.

FXR agonist 17 (Compound 10) (0.5-100 μM; 25 h) exhibits no cytotoxicity in RAW264.7 mouse macrophages at concentrations up to 40 μM, but reduces cell viability at concentrations of 60 μM and above. At 5-20 μM for 25 hours, FXR agonist 17 mitigates LPS-induced inflammation in RAW264.7 cells in a dose-dependent manner by activating FXR, significantly decreasing nitrite, TNF-α, and ROS levels, and regulating bile acid metabolism and inflammation-related gene expression. The IC50 values of FXR agonist 17 over 25 hours in HEK-293, HepG2, and HEK-293T cells are 62.2 μM, 57 μM, and 46.3 μM, respectively.

FXR agonist 17 (Compound 10) administered at 20 mg/kg orally once daily for 5 days significantly alleviates cholestatic liver injury in male C57BL/6 mice treated with ANIT. When given at the same dose and schedule over 28 days, it markedly reduces hepatic fibrosis in male C57BL/6 mice exposed to CCl4. Additionally, FXR agonist 17 improves liver histopathology in male C57BL/6 mice when administered once daily at 20 mg/kg for 28 consecutive days during weeks 8 to 12 of a 12-week induction period.