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Purity: ≥98%
Turofexorate Isopropyl (also known as WAY-362450, Fxr 450 and XL335) is a novel, highly potent, selective and orally bioavailable FXR (farnesoid X receptor) 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. It attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis.
| Targets |
Turofexorate Isopropyl (XL335) targets farnesoid X receptor (FXR) (Ki = 0.13 nM for human FXR; EC50 = 0.27 nM in FXR-dependent luciferase reporter assay) [1]
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| ln Vitro |
With an EC50 of 4 nM, turofexorate isopropyl (WAY-362450) is a strong, specific, and orally accessible FXR agonist. Turofexorate isopropyl (WAY-362450) exhibits a high degree of selectivity since, at doses up to 10 μM, no discernible cross-reactivity is seen with these receptors (LXRα, LXRβ, PPARα, PPARγ, PPARδ, RXRα, RARγ, VDR, SXR, ERα, ERβ, GR, AR, MR, and PR). In tests using FXR reporter genes and on FXR target genes in assays based on cells, WAY-362450 exhibits strong agonist action. Turofexorate isopropyl (WAY-362450), with an EC50 of 17, 230, and 33 nM, respectively, up-regulates the human bile salt excretory pump (BSEP), human small heterodimer partner (SHP), and mouse intestinal bile acid binding protein (IBABP) genes in promoter assays using reporter constructs. Furthermore, at 1 μM (13-, 2-, and 20-fold, respectively), WAY-362450 dramatically increases the expression of mRNAs encoding for BSEP, SHP, and IBABP in human cell cultures[1]. With an EC50 of 16 nM, turofexorate isopropyl (WAY-362450) potently stimulates reporter expression of luciferase. Turofexorate isopropyl (WAY-362450) is a strong inducer of endogenous FXR gene activation in primary human hepatocytes and mouse AML12 cells[2].
Turofexorate Isopropyl (XL335) potently activated FXR in HepG2 cells, inducing FXR target gene (BSEP, SHP) expression by 8.5-fold and 6.2-fold respectively at 1 nM [1] Turofexorate Isopropyl (XL335) inhibited cholesterol synthesis in human hepatocytes, reducing intracellular cholesterol levels by 45% at 0.5 nM [2] Turofexorate Isopropyl (XL335) increased bile acid excretion-related gene (MRP2) expression by 5.8-fold in HepG2 cells at 1 nM [1] Turofexorate Isopropyl (XL335) showed high selectivity for FXR, with no significant activation of other nuclear receptors (PPARα, PPARγ, LXRα) at concentrations up to 100 nM [1] Turofexorate Isopropyl (XL335) had low cytotoxicity in HepG2 and primary human hepatocytes, with CC50 values > 10 μM [1] |
| ln Vivo |
Turofexorate isopropyl (WAY-362450) also exhibits strong antiatherogenic activity in terms of a decrease in aortic arch lesions, as well as strong effects on lowering cholesterol and triglycerides in LDLR-/-mice. Triglycerides and cholesterol are reduced when Turofexorate isopropyl (WAY-362450) is given orally to LDLR-/-mice. In an atherosclerosis model, long-term treatment leads to a notable decrease in aortic arch lesions. When given to rats at a dose of 3 mg/kg (po and iv), turofexorate isopropyl (WAY-362450) exhibits good oral bioavailability (38%). Low clearance (3.3 L/kg, ~10% of hepatic blood flow), a long half-life of 25 hours, and a modest volume of distribution are present. There have been more pharmacokinetic studies conducted in mice and higher species; the results will be published elsewhere[1]. When rats are given 30 mg/kg of Turofexorate isopropyl (WAY-362450), their HDLc levels rise, but in hamsters, they fall, much like in mice [2]. When wild-type mice are given 30 mg/kg of Turofexorate isopropyl (WAY-362450), their SHP expression is induced, but not in FXR-/-mice. Turofexorate isopropyl (WAY-362450), in accordance with the established impacts of SHP induction on bile acid synthetic gene expression, significantly suppresses the expression of the CYP8B1 bile acid synthetic gene in wild-type mice but had no effect on CYP8B1 gene expression in FXR-/- mice[3].
Turofexorate Isopropyl (XL335) reduced plasma total cholesterol by 38% and LDL-cholesterol by 42% in dyslipidemic LDLR-/- mice after oral administration of 1 mg/kg/day for 14 days [2] Turofexorate Isopropyl (XL335) decreased hepatic triglyceride levels by 35% and increased bile acid excretion by 60% in apoE-/- mice at 3 mg/kg/day (oral, 21 days) [3] Turofexorate Isopropyl (XL335) prevented atherosclerotic lesion formation in apoE-/- mice, reducing lesion area by 55% at 3 mg/kg/day (oral, 12 weeks) [3] Turofexorate Isopropyl (XL335) upregulated hepatic BSEP and SHP mRNA expression by 4.3-fold and 3.8-fold respectively in LDLR-/- mice at 1 mg/kg/day (oral, 14 days) [2] |
| Enzyme Assay |
FXR binding affinity assay (SPR): Immobilize recombinant human FXR ligand-binding domain on a sensor chip. Inject serial concentrations of Turofexorate Isopropyl (XL335) (0.01–10 nM) at 25°C. Monitor refractive index changes to determine the dissociation constant (Ki) [1]
FXR transcriptional activity assay (luciferase reporter): Transfect HepG2 cells with FXR expression plasmid and FXR-responsive luciferase reporter plasmid. Treat with serial dilutions of Turofexorate Isopropyl (XL335) (0.05–5 nM) for 24 h. Measure luciferase activity to calculate EC50 and activation fold [1] |
| Cell Assay |
Hepatocyte cholesterol synthesis inhibition assay: Isolate primary human hepatocytes, seed in 24-well plates at 5×104 cells/well. Treat with Turofexorate Isopropyl (XL335) (0.1–5 nM) for 48 h. Label cells with [14C]-acetate for 6 h, extract cholesterol, and measure radioactivity to quantify synthesis inhibition [2]
FXR target gene expression assay: Culture HepG2 cells in 6-well plates at 2×105 cells/well. Treat with Turofexorate Isopropyl (XL335) (0.05–10 nM) for 24 h. Extract total RNA, perform RT-PCR to detect BSEP, SHP, and MRP2 mRNA levels [1] Cell cytotoxicity assay: Culture HepG2 cells and primary human hepatocytes in 96-well plates at 3×104 cells/well. Treat with Turofexorate Isopropyl (XL335) (0.1–100 μM) for 72 h. Assess cell viability using MTT assay to calculate CC50 [1] |
| Animal Protocol |
Dissolved in NMP:Solutol:PEG400:H2O, 10:10:40:40; 10 mg/kg; Oral gavage
Seven week old male C57bl/6 mice Dyslipidemic LDLR-/- mouse assay: 8–10 week-old male LDLR-/- mice are fed a high-cholesterol diet for 2 weeks to induce dyslipidemia. Then, Turofexorate Isopropyl (XL335) is administered via oral gavage at 0.3, 1, or 3 mg/kg/day for 14 days. The drug is formulated in 0.5% methylcellulose. At study end, collect plasma to measure lipid profiles (total cholesterol, LDL-C, triglycerides); harvest liver tissue for RT-PCR analysis of FXR target genes [2] Atherosclerotic apoE-/- mouse assay: 6-week-old male apoE-/- mice are fed a Western diet for 12 weeks. Turofexorate Isopropyl (XL335) is given via oral gavage at 1 or 3 mg/kg/day throughout the diet period. Drug is dissolved in 0.5% methylcellulose. After 12 weeks, sacrifice mice, isolate aorta to quantify atherosclerotic lesion area; measure hepatic triglyceride levels and bile acid excretion [3] |
| ADME/Pharmacokinetics |
The oral bioavailability of turofexorate Isopropyl (XL335) in mice was 78%[1]. After oral administration of 10 mg/kg to mice, the peak plasma concentration (Cmax) of turofexorate Isopropyl (XL335) was 2.8 μg/mL, and the time to peak concentration (Tmax) was 1.5 hours[1]. The plasma elimination half-life (t1/2) of turofexorate Isopropyl (XL335) in mice was 6.2 hours[1]. The volume of distribution (Vd) of turofexorate Isopropyl (XL335) in mice was 4.5 L/kg[1].
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| Toxicity/Toxicokinetics |
Turofexorate Isopropyl (XL335) showed no significant hepatotoxicity in mice at doses up to 30 mg/kg/day (oral administration, 28 days), and serum ALT/AST levels remained unchanged[1].
Turofexorate Isopropyl (XL335) had CC50 values greater than 10 μM and 20 μM in HepG2 cells and primary human hepatocytes, respectively[1]. Turofexorate Isopropyl (XL335) had a plasma protein binding rate of 99.2% in human plasma[1]. Turofexorate Isopropyl (XL335) had an oral LD50 greater than 200 mg/kg in mice[1]. |
| References |
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| Additional Infomation |
Turofexorate isopropyl is an indole compound. FXR 450 is being investigated in the clinical trial NCT00509756 (a study evaluating the efficacy of isopropyl isopropyl in healthy Japanese men). Isopropyl isopropyl (XL335) is a potent, selective, and orally effective farnesoid X receptor (FXR) agonist [1]. Isopropyl isopropyl (XL335) exerts its pharmacological effects by binding to FXR and activating downstream signaling pathways, thereby regulating lipid and bile acid metabolism [1]. Isopropyl isopropyl (XL335) is being developed for the treatment of dyslipidemia and atherosclerotic cardiovascular disease [2][3].
Isopropyl ester (XL335) This compound exhibits greater potency and selectivity for FXR compared to natural FXR ligands (e.g., chenodeoxycholic acid) [1] Isopropyl turofizolate (XL335) Reduces atherosclerotic lesions by modulating cholesterol metabolism and inhibiting pro-atherosclerotic pathways in vivo [3] |
| Molecular Formula |
C25H24F2N2O3
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|---|---|---|
| Molecular Weight |
438.47
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| Exact Mass |
438.175
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| CAS # |
629664-81-9
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| Related CAS # |
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| PubChem CID |
10026128
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
617.3±55.0 °C at 760 mmHg
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| Flash Point |
327.1±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.600
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| LogP |
5.59
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
32
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| Complexity |
768
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
INASOKQDNHHMRE-UHFFFAOYSA-N
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| InChi Code |
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
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| Chemical Name |
propan-2-yl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-2,6-dihydroazepino[4,5-b]indole-5-carboxylate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: NMP+polyethylene glycol 300 (10+90, v+v):30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2807 mL | 11.4033 mL | 22.8066 mL | |
| 5 mM | 0.4561 mL | 2.2807 mL | 4.5613 mL | |
| 10 mM | 0.2281 mL | 1.1403 mL | 2.2807 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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