Table 1.
Novel candidate compounds for farnesoid X receptor (FXR) agonism/activation. ANIT—α-naphthylisothiocyanate; BA—bile acid; BSEP—bile salt export pump; CAR—constitutive androstane receptor; ER—estrogen receptor; GR—glucocorticoid receptor; HFD—high-fat diet; HSC—hepatic stellate cells; LXR—liver X receptor; NASH—nonalcoholic steatohepatitis; PPAR—peroxisome proliferator-activated receptor; RAR—retinoic acid receptor; ROR—RAR-related orphan receptor; SHP—small heterodimer partner; TGF—transforming growth factor.
| Study Type | Compound | Chemical Properties | Proposed Mode of Actions (MOAs) for FXR Modulation | Biological Effects Potentially through FXR Modulation | References |
|---|---|---|---|---|---|
| Preclinical | Alisol B 23-acetate (AB23A) | Natural triterpenoid | Direct interaction (molecular docking analysis) | - Promotes liver regeneration in mice after partial hepatectomy - Protects against ANIT-induced hepatotoxity and cholestasis in mice - Protects against CCl4-induced hepatotoxicity in mice - Protects against estrogen-induced cholestatic liver injury in mice - Prevents methionine and choline-deficient diet-induced NASH in mice Note: also suggested to have ligand binding activity of PXR, but not CAR, LXR, FXR, PPARα, PPARδ and PPARγ [138] |
[139,140,141,142,143] |
| Preclinical | Curcumin | Natural polylphenol | - Direct interaction (molecular docking analysis) - FXR gene induction by Nrf2 pathway |
- Attenuates ethanol-induced hepatotoxicity and lipid accumulation in hepatocytes - Protects against ANIT-induced cholestasis in mice - Attenuates hepatic steatosis in high-fat and high-fructose diet-fed mice |
[64,144,145] |
| Preclinical | Silymarin | Natural flavonoid | Direct interaction (molecular docking analysis) | - Ameliorate insulin resistance, dyslipidemia and inflammation, and reconstitutes the BA pool in liver of HFD-induced obesity in mice | [146] |
| Preclinical | Hedragonic acid | Natural triterpene | Direct interaction (molecular docking analysis) | - Protects against acetaminophen-induced liver injury and inflammation in mice | [147] |
| Preclinical | Dihydro-artemisinin | Active metabolite of artemisinin compounds | FXR gene induction (mRNA and protein) | - Restricts HSC contraction - Counteracts fibrotic portal hypertension in CCl4-treated rats - Protects against alcoholic liver injury and hepatic steatosis in rats |
[148,149,150] |
| Preclinical | Altenusin | Nonsteroidal microbial metabolite | Ligand binding activity of FXR using GAL4-hFXR-LBD (but not PPARα/β/γ, LXRα/β, RXR, ERα, GR, RARα/β/γ, RORα/β/γ) |
- Protects against HFD-induced obesity, hyperglycemia, and hepatic steatosis in mice | [151] |
| Preclinical /Clinical |
PX20606 (PX-102) |
Nonsteroidal synthetic | Selective FXR agonist | - Induces high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys - Ameliorates portal hypertension by reducing liver fibrosis, vascular remodeling and sinusoidal dysfunction in CCl4-treated rats - Phase I studies (NCT01998659, NCT01998672) |
[152,153] |
| Preclinical | Tropifexor (LJN452) | Nonsteroidal synthetic | Selective FXR agonist | - Induces FXR target genes in the liver and ileum (e.g., SHP, BSEP, and FGF15), and reduces serum triglycerides in rats | [154] |
| Preclinical | BAR704 | Steroidal synthetic | Selective FXR agonist | - Reduces liver fibrosis by interfering with the TGF-Smad3 pathway in HSCs | [155] |
| Preclinical | BAR502 | Non-BA steroidal synthetic | Dual agonist of FXR and TGR5 | - Promotes browning of white adipose tissue and reverses liver steatosis and fibrosis in mice fed HFD and fructose | [156] |