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XL335 (Synonyms: FXR 450, Turofexorate Isopropyl, WAY-362450)

Catalog No.GC10760

XL335 (FXR-450) is a potent, selective, and orally bioavailable FXR agonist with EC50 of 4 nM.

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XL335 Chemical Structure

Cas No.: 629664-81-9

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10mM (in 1mL DMSO)
$80.00
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5mg
$72.00
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10mg
$99.00
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50mg
$315.00
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100mg
$495.00
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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment:

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[2].

Animal experiment:

Mice[3] Age- and sex-matched 8- to 12-week-old mice are fed standard chow and housed in temperature-controlled virus-free facility on a 12-h-light/dark cycle with free access to food and water. Where indicated, mice are fed either a Western diet containing 42% fat and 0.2% cholesterol by weight or this Western diet supplemented to contain 0.225 mg Turofexorate isopropyl (WAY-362450) per gram of diet. The mice consumed ~4 g diet per day, resulting in the delivery of ~30 mg of Turofexorate isopropyl (WAY-362450) per kg of body weight, assuming a 30 g body weight. Animals are maintained on these diets for 6 (apoE-/-) or 12 weeks (LDLR-/-). At the end of each study, animals are euthanized and blood samples collected via the orbital eye for lipid analysis. Liver and ileum tissue are removed for mRNA quantification, and aortas are removed and stored in 10% buffered formalin solution. Rats[2] Eight-week-old male Sprague Dawley rats and Syrian Golden hamsters are fed a 60% fructose/0.15% cholesterol diet. For the rat study, the rats are placed onto the diet for 2 wk and then treated by daily oral gavage with vehicle (80% polyethylene glycol/20% Tween) or varying concentrations of Turofexorate isopropyl (WAY-362450) (8/group) as indicated for 7 days (8 rats/group). The hamster study is conducted as a preventative treatment, so both the diet and drug treatments are initiated on day 1 and continued for 21 days (8 hamsters/group). On the last day after the final dose, the food is removed to allow a 3 h fast, and serum and liver are harvested for analysis as described above.

References:

[1]. Flatt B, et al. Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem. 2009 Feb 26;52(4):904-7.
[2]. Evans MJ, et al. A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G543-52.
[3]. Hartman HB, et al. Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. J Lipid Res. 2009 Jun;50(6):1090-100.

Background

XL335 is a potent, selective and orally bioavailable agonist of the farnesoid X receptor (FXR) with EC50 value of 4 nM [1].

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 [2].

Additionally, in hepatoma cells, XL335 block the lipid accumulation induced by palmitic acid (PA). In vivo, XL335 has shown to decrease portal vein endotoxin level and reduce inflammation induced by fructose in mice. XL335 attenuated inflammation and suppressed ADRP expression in lipopolysaccharide (LPS)-induced mice [3].

References:
[1] Flatt B1, Martin R, Wang TL, Mahaney P, Murphy B, Gu XH, Foster P, Li J, Pircher P, Petrowski M, Schulman I, Westin S, Wrobel J, Yan G, Bischoff E, Daige C,Mohan R. Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem. 2009 Feb 26;52(4):904-7. doi: 10.1021/jm8014124.
[2] Zhang S1, Liu Q, Wang J, Harnish DC. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists. Biochem Biophys Res Commun. 2009 Feb 6;379(2):476-9.
[3] Liu X1, Xue R2, Ji L1, Zhang X1, Wu J3, Gu J1, Zhou M4, Chen S5. Activation of farnesoid X receptor (FXR) protects against fructose-induced liver steatosis via inflammatory inhibition and ADRP reduction. Biochem Biophys Res Commun. 2014 Jul 18;450(1):117-23.

Chemical Properties

Cas No. 629664-81-9 SDF
Synonyms FXR 450, Turofexorate Isopropyl, WAY-362450
Chemical Name propan-2-yl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-2,6-dihydroazepino[4,5-b]indole-5-carboxylate
Canonical SMILES CC(C)OC(=O)C1=CN(CC(C2=C1NC3=CC=CC=C32)(C)C)C(=O)C4=CC(=C(C=C4)F)F
Formula C25H24F2N2O3 M.Wt 438.48
Solubility ≥ 20.4mg/mL in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 2.2806 mL 11.403 mL 22.8061 mL
5 mM 0.4561 mL 2.2806 mL 4.5612 mL
10 mM 0.2281 mL 1.1403 mL 2.2806 mL
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Average Rating: 5 ★★★★★ (Based on Reviews and 26 reference(s) in Google Scholar.)

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