product name Turofexorate Isopropyl (XL335)
Description: Turofexorate Isopropyl (also known as WAY-362450, Fxr 450 and XL335) is a potent, selective FXR agonist with EC50 of 4 nM, it is highly selective versus other nuclear receptors, such as LXR, PPAR, ER and etc. XL335 has shown to reduce IL-6-induced both mRNA and protein expression of CRP via FXR in human hepatoma Hep3B cells. XL335 remarkably reduced LPS-induced SAP and SAA3 mRNA expression in WT mice, but not in FXR/KO mice.
References: J Med Chem. 2009 Feb 26;52(4):904-7.
438.47
Formula
C25H24F2N2O3
CAS No.
629664-81-9
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 33 mg/mL (75.3 mM)
Water: <1 mg/mL
Ethanol: 2 mg/mL (4.6 mM)
Solubility (In vivo)
NMP+polyethylene glycol 300 (10+90, v+v): 30 mg/mL
Synonyms
Fxr 450
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19421570
| In Vitro |
In vitro activity: WAY-362450 binds to the ligand-binding domain (LBD) of human FXR. WAY-362450 resides in a predominately hydrophobic pocket with only a few polar atoms making contact with WAY-362450. WAY-362450 promotes transcription of the human BSEP, human SHP, and mouse IBABP genes utilizing reporter constructs with EC50 of 17, 230, and 33 nM, respectively in promoter assays. WAY-362450 at concentration of 1 μM significantly induces mRNAs encoding for BSEP, SHP, and IBABP in human cell cultures to 13-, 2-, and 20-fold, respectively. WAY-362450 at concentration of 1 μM suppresses interleukin-6-induced CRP expression in human Hep3B hepatoma cells, and the inhibitory effect is attenuated when knockdown of FXR by short interfering RNA. Kinase Assay: Cell Assay: |
|---|---|
| In Vivo | WAY-362450 administrated intravenously or orally at does of 3 mg/kg in rats with a protracted half-life of 25 h, modest volume of distribution, and low clearance of 3.3 L/kg. WAY-362450 administered orally at dose of 10 mg/kg in normal C57bl/6 mice for a period of 7 days significantly lowers triglycerides to 62.0 ± 6.4 mg/dL and total cholesterol to 78.1 ± 5.0 mg/dL. WAY-362450 administered orally at dose of 1 and 3 mg/kg daily for 6 weeks in LDLR−/− mice, triglycerides is lowered by 19% and 39%, respectively, total cholesterol is lowered by 23% and 50%, respectively and lesion formation by 18% and 36%, respectively. WAY-362450 intraperitoneally administrated at dose of 30 mg/kg daily for 4 days in wild type C57BL/6 mice attenuates lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver. WAY-362450 orally administered at dose of 30 mg/kg/day for 4 weeks in adult male C57BL/6 mice reduces inflammatory cell infiltration and hepatic fibrosis, the reduction in inflammatory cell infiltration correlates with deceased serum levels of keratinocyte derived chemokine (mKC) and MCP 1 and decreased hepatic gene expression of MCP-1 and VCAM-1, and the reduction of hepatic fibrosis by WAY-362450 treatment corresponded to a reduction in hepatic gene expression of fibrosis markers. WAY-362450 administrated orally at dose of 30mg/kg in LDLR−/− and apoE−/− mice blocks diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation, WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7α-hydroxylase (CYP7A1) and sterol 12 α-hydroxylase (CYP8B1) expression |
| Animal model | Seven week old male C57bl/6 mice |
| Formulation & Dosage | Dissolved in NMP:Solutol:PEG400:H2O, 10:10:40:40; 10 mg/kg; Oral gavage |
| References | J Med Chem. 2009 Feb 26;52(4):904-7. |
