Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C28H22Cl3NO4 |
| Molecular Weight | 542.838 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)C1=C(COC2=CC=C(\C=C\C3=CC(=CC=C3)C(O)=O)C(Cl)=C2)C(=NO1)C4=C(Cl)C=CC=C4Cl
InChI
InChIKey=BYTNEISLBIENSA-MDZDMXLPSA-N
InChI=1S/C28H22Cl3NO4/c1-16(2)27-21(26(32-36-27)25-22(29)7-4-8-23(25)30)15-35-20-12-11-18(24(31)14-20)10-9-17-5-3-6-19(13-17)28(33)34/h3-14,16H,15H2,1-2H3,(H,33,34)/b10-9+
| Molecular Formula | C28H22Cl3NO4 |
| Molecular Weight | 542.838 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 1 |
| Optical Activity | NONE |
GW-4064 is a synthetic small molecule selective agonist of the orphan nuclear receptor FXR developed by GlaxoSmithKline. GW-4064-mediated FXR activation ameliorates diet-induced obesity, suppresses hepatic lipid accumulation, and maintains glucose and lipid homeostasis in C57BL/6 mice. GW-4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligand GW-4064 might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL2047 |
65.0 nM [EC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
|||
| Preventing | Unknown Approved UseUnknown |
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| Primary | Unknown Approved UseUnknown |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. | 2015-09 |
|
| Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression. | 2015-02-27 |
|
| Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. | 2014-08-01 |
|
| Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. | 2013-02 |
|
| Modulation of farnesoid X receptor results in post-translational modification of poly (ADP-ribose) polymerase 1 in the liver. | 2013-01-15 |
|
| Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19. | 2012-10 |
|
| Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. | 2012-09 |
|
| A tea catechin, epigallocatechin-3-gallate, is a unique modulator of the farnesoid X receptor. | 2012-01-15 |
|
| Tissue specific induction of p62/Sqstm1 by farnesoid X receptor. | 2012 |
|
| Farnesoid X receptor induces murine scavenger receptor Class B type I via intron binding. | 2012 |
|
| Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice. | 2011-04 |
|
| Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. | 2011-04 |
|
| Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene. | 2011-02-15 |
|
| The evolution of farnesoid X, vitamin D, and pregnane X receptors: insights from the green-spotted pufferfish (Tetraodon nigriviridis) and other non-mammalian species. | 2011-02-03 |
|
| Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro. | 2010-07-01 |
|
| Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids. | 2010-04 |
|
| Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine. | 2010-04 |
|
| Exposure to the synthetic FXR agonist GW4064 causes alterations in gene expression and sublethal hepatotoxicity in eleutheroembryo medaka (Oryzias latipes). | 2010-02-15 |
|
| Differentiated CaCo-2 cells as an in-vitro model to evaluate de-novo apolipoprotein A-I production in the small intestine. | 2009-06 |
|
| Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy. | 2009-03 |
|
| The farnesoid X receptor FXRalpha/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution. | 2007-09 |
|
| Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase. | 2006-08 |
|
| Bile acids induce adhesion molecule expression in endothelial cells through activation of reactive oxygen species, NF-kappaB, and p38. | 2006-08 |
|
| Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells. | 2006-02-03 |
|
| A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids. | 2006-02 |
|
| Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. | 2005-10 |
|
| VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. | 2005-09 |
|
| The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. | 2005-08 |
|
| Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. | 2005-05 |
|
| Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. | 2004-08 |
|
| The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. | 2004-03-05 |
|
| Farnesoid X receptor activates transcription of the phospholipid pump MDR3. | 2003-12-19 |
|
| Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. | 2003-12 |
|
| Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. | 2003-03-21 |
|
| Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding. | 2003-03-21 |
|
| Identification of a chemical tool for the orphan nuclear receptor FXR. | 2000-08-10 |
Patents
Sample Use Guides
Mice: Fifteen week-old C57BL/6 mice fed with high-fat diet (HFD) or high-fat, high-cholesterol diet were treated by twice weekly injection of GW-4064 (50 mg/kg) intraperitoneally or DMSO (carrier solution) for 6 weeks. Activation of FXR by GW-4064 suppressed weight gain in C57BL/6 mice fed with either HFD or high-fat and high-cholesterol diet.
Route of Administration:
Intraperitoneal
In Vitro Use Guide
Curator's Comment: GW-4064 (5 umol/L; 24 h), a specific FXR agonist, induced nuclear translocation of the receptor in T84 cells and attenuated Cl(-) secretory responses to both Ca(2+) and cAMP-dependent agonists. GW-4064 also prevented agonist-induced inhibition of NHE3 in Caco-2 cells. https://www.ncbi.nlm.nih.gov/pubmed/23916961
GW-4064 is a full agonist with EC50 values of 80 and 90 nM, respectively, in CV-1 cells transfected with mouse and human FXR expression vectors and an established reporter gene. There is no activity of GW-4064 on other nuclear receptors, including the retinoic acid receptor, at concentrations up to 1 uM.
| Substance Class |
Chemical
Created
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admin
on
Edited
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| Record UNII |
SR225WUZ0H
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| Record Status |
Validated (UNII)
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