Farnesoid X receptor (FXR) is a nuclear hormone receptor critically involved in the regulation of bile acid homeostasis. It is now recognized that bile acids serve as the natural ligands for FXR. Once activated, FXR in turn induces the expression of another nuclear hormone receptor, small heterodimer partner (SHP).
FXR, which is highly expressed in the liver, intestine, kidney, adrenal glands, and adipose tissue, is a master regulator of the synthesis and pleiotropic actions of endogenous bile acids (BAs).
FXR activation inhibits BA synthesis and has anti-inflammatory effects in atherosclerosis, inflammatory bowel disease, and experimental cholestasis, whereas TGR5 activation, via cAMP-mediated pathways, reduces proinflammatory cytokine production in macrophages and Kupffer cells.
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A potent and selective FXR agonist with EC50 of 15 nM in cell-free assay, >200-fold more potent than CDCA; has an EC50 of 80 and 90 nM, respectively, in CV-1 cells transfected with mouse and human FXR expression vectors; significantly reducess serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage in rat models of cholestasis.
GSK-2324 (GSK2324) is a potent, selective, full FXR agonist with EC50 of 120 nM in FRET assay; lowers body weight gain and serum glucose in a DIO mouse model of diabetes.
LY-2562175 (LY2562175, LY 2562175) is a novel potent, selective, partial FXR agonist with EC50 of 193 nM; does not promote transcriptional activation of other nuclear receptor, such as GR, PR, MR and AR (EC50>10 uM); lowers LDL and triglycerides while raising HDL in preclinical species.
INT-767 is a potent, selective, dual farnesoid X receptor (FXR) and TGR5 agonist with EC50 of 30 and 630 nM, respectively; fails to activate 15 other nuclear receptors involved in metabolic pathways, and does not inhibit cytochrome P450 enzymes; induces FXR-dependent lipid uptake by adipocytes and promotes TGR5-dependent glucagon-like peptide-1 (GLP-1) secretion by enteroendocrine cells; markedly decreases cholesterol and triglyceride levels in diabetic db/db mice.
INT-747(Obeticholic acid, 6-ECDCA, 6-Ethylchenodeoxycholic acid) is a potent and selective FXR agonist (EC50=99 nM); possesses anticholeretic activity in rat model of cholestasis.
Fexaramine is a potent, specific FXR agonist with EC50 of 25 nM, more efficacious ligand for FXR than GW4064; shows no transcriptional activity against hRXRα, hPPARα/γ/δ, mPXR, hPXR, hLXRα, hTRβ, hRARβ, mCAR, mERRγ, and hVDR; strongly induces target genes SHP, PLTP BSEP, and MRP-2 in the HEPG2 liver cell system; robustly induces FGF15, leading to alterations in BA composition.
Tropifexor (LJN-452, LJN452) is a novel highly potent, selective, orally acitive FXR full agonist with EC50 of 0.26 nM; shows no significant off-target activity (>10,000-fold selectivity for FXR) in a panel of targets, including TGR5 (>10 uM); demonstratesin vivo activity in rodent PD models, and shows potential for treatment of cholestatic liver diseases and NASH.
MFA-1 (Merck FXR agonist 1) is a potent, synthetic FXR agonist with EC50 of 16.9 nM in coactivator recruitment assays, displays 500-fold more potent than CDCA; displays an unexpected mode of binding and activation to FXR.
Cilofexor (GS-9674, GS9674, PX-104) is a novel specific, non-steroidal farnesoid X receptor (FXR) agonist that reduces liver fibrosis and ameliorates portal hypertension in rat NASH models.
Nidufexor (LMB763, LMB-763) is a novel potent farnesoid X receptor (FXR) agonist for the treatment of non-alcoholic steatohepatitis (NASH) and hepatobiliary disorders.
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