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XL335

FXR agonist CAS# 629664-81-9

XL335

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Quality Control of XL335

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Chemical structure

XL335

3D structure

Chemical Properties of XL335

Cas No. 629664-81-9 SDF Download SDF
PubChem ID 10026128 Appearance Powder
Formula C25H24F2N2O3 M.Wt 438.48
Type of Compound N/A Storage Desiccate at -20°C
Synonyms XL335; Turofexorate isopropyl
Solubility DMSO : 25 mg/mL (57.02 mM; Need ultrasonic)
Chemical Name propan-2-yl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-2,6-dihydroazepino[4,5-b]indole-5-carboxylate
SMILES CC(C)OC(=O)C1=CN(CC(C2=C1NC3=CC=CC=C32)(C)C)C(=O)C4=CC(=C(C=C4)F)F
Standard InChIKey INASOKQDNHHMRE-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H24F2N2O3/c1-14(2)32-24(31)17-12-29(23(30)15-9-10-18(26)19(27)11-15)13-25(3,4)21-16-7-5-6-8-20(16)28-22(17)21/h5-12,14,28H,13H2,1-4H3
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of XL335

DescriptionWAY-362450 is a potent, selective, and orally bioavailable FXR agonist with EC50 of 4 nM.In Vitro:WAY-362450 is a potent, selective, and orally bioavailable FXR agonist (EC50=4 nM). WAY-362450 is highly selective, as no significant cross-reactivity with these receptors (LXRα, LXRβ, PPARα, PPARγ, PPARδ, RXRα, RARγ, VDR, SXR, ERα, ERβ, GR, AR, MR, and PR) is observed at concentrations up to 10 μM. WAY-362450 displays potent agonist activity in the FXR reporter gene assays and on FXR target genes in cell-based assays. In promoter assays, utilizing reporter constructs under control of the human bile salt excretory pump (BSEP), human small heterodimer partner (SHP), and mouse intestinal bile acid binding protein (IBABP) genes are up-regulated by WAY-362450 with EC50 of 17, 230, and 33 nM, respectively. In addition, WAY-362450 significantly induces mRNAs encoding for BSEP, SHP, and IBABP in human cell cultures at 1 μM (13-, 2-, and 20-fold, respectively)[1]. WAY-362450 potently induces luciferase reporter expression with an EC50 of 16 nM. WAY-362450 is a potent stimulator of endogenous FXR gene activation in mouse AML12 cells and in primary human hepatocytes[2].In Vivo:WAY-362450 also shows potent effects on cholesterol and triglyceride lowering in LDLR-/- mice and antiatherogenic activity with respect to reduction of aortic arch lesions. Oral administration of WAY-362450 to LDLR-/- mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions. WAY-362450 is dosed in rat at 3 mg/kg (po and iv) and shows good oral bioavailability (38%). There is a protracted half-life of 25 h, modest volume of distribution, and low clearance (3.3 L/kg, ~10% of hepatic blood flow). Additional pharmacokinetic studies in mice and higher species have been completed, and the data will be reported elsewhere[1]. In rats, WAY-362450 results in an elevation in HDLc levels, whereas in hamsters it causes a reduction similar to that observed in mice[2] Treatment of wild-type mice with 30 mg/kg WAY-362450 results in induction of SHP expression in wild-type mice but not in FXR-/- mice. Consistent with the known effects of SHP induction on bile acid synthetic gene expression, WAY-362450 strongly represses expression of the CYP8B1 bile acid synthetic gene in wild-type mice but had no effect on CYP8B1 gene expression in FXR-/- mice[3].

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.

Protocol

Cell Assay [2]
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 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 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 Administration [3][2]
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 WAY-362450 per gram of diet. The mice consumed ~4 g diet per day, resulting in the delivery of ~30 mg of 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 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.

XL335 Dilution Calculator

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Preparing Stock Solutions of XL335

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2806 mL 11.403 mL 22.8061 mL 45.6121 mL 57.0151 mL
5 mM 0.4561 mL 2.2806 mL 4.5612 mL 9.1224 mL 11.403 mL
10 mM 0.2281 mL 1.1403 mL 2.2806 mL 4.5612 mL 5.7015 mL
50 mM 0.0456 mL 0.2281 mL 0.4561 mL 0.9122 mL 1.1403 mL
100 mM 0.0228 mL 0.114 mL 0.2281 mL 0.4561 mL 0.5702 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on XL335

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.

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References on XL335

Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR).[Pubmed:19159286]

J Med Chem. 2009 Feb 26;52(4):904-7.

Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.

Description

Turofexorate isopropyl (WAY-362450) is a potent, selective, and orally bioavailable FXR agonist with EC50 of 4 nM.

Keywords:

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