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Turofexorate Isopropyl(XL335)
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Turofexorate Isopropyl(XL335)图片
CAS NO:629664-81-9
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW)438.47
FormulaC25H24F2N2O3
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
SynonymsFxr 450; WAY-362450; WAY362450; WAY 362450; XL335; XL 335; XL-335; FXR-450; FXR 450; FXR450
实验参考方法
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.


Cell Assay: Mouse AML12 cells are plated at 200,000 cells/well on the 24-well plate in 1 mL of growth medium [DMEM/F12 10% FBS, 1% penicillin and streptomycin, 1% insulin-transferrin-selenium-G supplement (ITS), 0.1% Dexamethasone (40 ng/mL)/well. The cells are treated with increasing concentrations of Turofexorate isopropyl (WAY-362450) (0.001, 0.01, 0.1, 1 and 10 μM) or GW4064 for 24 h. Total RNA is prepared and analyzed by real-time RT-PCR, and short heterodimer partner (SHP) expression is normalized to GAPDH and reported as fold induction vs. vehicle-treated cells. Preplated 24-well plates of human male primary hepatocytes with matrigel overlay are obtained from Cellz Direct. Cells are maintained in serum-free Williams medium E and supplemented with penicillin/streptomycin, dexamethasone, ITS, L-glutamine, and HEPES buffer. They are treated overnight with vehicle (0.01% DMSO) or increasing concentrations of Turofexorate isopropyl (WAY-362450) or GW4064. Total RNA is purified using the Qiagen RNeasy clean kit, and gene expression is quantified by real-time RT-PCR with the Qiagen Quantitech kit using an ABI 7900. The relative amount of mRNA is normalized to 18S ribosomal RNA, and data shown represent an average of two independent experiments.

In VivoWAY-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 modelSeven week old male C57bl/6 mice
Formulation & DosageDissolved in NMP:Solutol:PEG400:H2O, 10:10:40:40; 10 mg/kg; Oral gavage
ReferencesJ Med Chem. 2009 Feb 26;52(4):904-7.