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| Targets |
AS1708727 targets Foxo1 (forkhead box O1), a transcription factor that plays a central role in the regulation of glucose and lipid metabolism. Foxo1 is involved in the regulation of gluconeogenesis, glycogenolysis, and lipogenesis. In the liver, Foxo1 promotes the expression of gluconeogenic genes, such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), leading to increased glucose production. AS1708727 is an orally active inhibitor of Foxo1. It inhibits Foxo1-mediated transcription of G6Pase and PEPCK with EC50 values of 0.33 µM and 0.59 µM, respectively. By inhibiting Foxo1, AS1708727 reduces the expression of gluconeogenic genes, thereby lowering blood glucose levels. It also improves triglyceride metabolism.
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| ln Vitro |
By suppressing the expression of the gluconeogenesis gene, AS1708727 prevents the rise in blood glucose levels [1].
In vitro studies have demonstrated that AS1708727 is a potent inhibitor of Foxo1-mediated transcription. It inhibits Foxo1 with EC50 values of 0.33 µM for G6Pase and 0.59 µM for PEPCK. The compound's ability to inhibit Foxo1 transcriptional activity has been confirmed in cell-based reporter assays. By inhibiting Foxo1, AS1708727 reduces the expression of gluconeogenic genes, which is expected to lower glucose production. These in vitro findings establish AS1708727 as a potent inhibitor of Foxo1 with potential anti-diabetic activity. |
| ln Vivo |
Oral AS1708727 (30 to 300 mg/kg) lowers triglyceride and blood sugar levels while also having antidiabetic actions [1].
In vivo studies have demonstrated that AS1708727 is orally active and reduces both blood glucose and triglyceride levels in diabetic mice. At oral doses of 30 to 300 mg/kg, AS1708727 reduces both blood glucose and triglyceride levels, exhibiting anti-diabetic effects. The compound's ability to inhibit Foxo1 and reduce gluconeogenesis contributes to its glucose-lowering effects. Its effects on triglyceride metabolism suggest that AS1708727 may also have lipid-lowering properties. These in vivo studies confirm that AS1708727 is a potent and orally active Foxo1 inhibitor with therapeutic potential for diabetes and metabolic disorders. |
| Enzyme Assay |
The in vitro assays for AS1708727 measure its inhibition of Foxo1 transcriptional activity. Cell-based reporter assays are commonly used to assess Foxo1 activity. In these assays, cells are transfected with a luciferase reporter gene under the control of a Foxo1-responsive promoter (e.g., containing insulin response sequences). Cells are treated with AS1708727, and luciferase activity is measured. The inhibition of Foxo1-mediated transcription is calculated, and the EC50 is determined. For AS1708727, the EC50 values for inhibition of G6Pase and PEPCK are 0.33 µM and 0.59 µM, respectively. These assays confirm that AS1708727 is a potent inhibitor of Foxo1 transcriptional activity.
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| Cell Assay |
RT-PCR[1]
Cell Types: Fao cells, derived from H4IIE liver cancer cell line. Tested Concentrations: 0.1-3000μM. Incubation Duration: 18 hrs (hours). Experimental Results: G6Pase and PEPCK mRNA levels diminished in a dose-dependent manner. In vitro cell-based assays for AS1708727 are used to study its effects on Foxo1-mediated gene expression. Hepatocytes or other relevant cell lines are treated with AS1708727, and the expression of Foxo1 target genes, such as G6Pase and PEPCK, is measured by quantitative PCR or Western blotting. The compound's ability to reduce the expression of these gluconeogenic genes is assessed. The effects on glucose production and lipid metabolism can also be measured in these cells. These cell-based assays confirm that AS1708727 inhibits Foxo1 activity and reduces gluconeogenic gene expression. |
| Animal Protocol |
Animal/Disease Models: Sixweeks old db/db mice[1].
Doses: 100-1000 mg/kg (pharmacokinetic/PK/PK analysis). Mode of Route of Administration: Orally. Experimental Results: Cmax) was 26.7 μM and maximum drug concentration time (Tmax) was 0.5 hrs (hrs (hours)) at 300 mg/kg [1]. The liver concentration of AS1708727 is 3.7 to 5.4 times higher than the plasma concentration 0.5-2 hrs (hrs (hours)) after oral administration, indicating good hepatic conversion of AS1708727 [1]. Animal/Disease Models: Diabetic model mouse[1]. Doses: 30 to 300 mg/kg. Route of Administration: Orally, twice (two times) daily for 4 days. Experimental Results: Blood glucose levels were Dramatically diminished at 300 mg/kg [1]. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are Dramatically diminished at 300 mg/kg [1]. G6Pase and PEPCK mRNA levels were Dramatically diminished at doses of 100 and 300 mg/kg [1]. In vivo animal experiments for AS1708727 are conducted in mouse models of diabetes, such as diet-induced obese mice or genetically diabetic mice (e.g., db/db mice). In a typical study, mice are treated with AS1708727 orally at doses of 30 to 300 mg/kg. Blood glucose and triglyceride levels are measured at various time points. The compound's ability to reduce blood glucose and triglyceride levels is assessed. Glucose tolerance tests or insulin tolerance tests may also be performed to evaluate the compound's effects on glucose metabolism. These studies provide evidence for the in vivo efficacy of AS1708727 as an anti-diabetic agent. |
| ADME/Pharmacokinetics |
AS1708727 has a molecular weight of 443.37 g/mol and a molecular formula of C24H24Cl2N2O2. It is a solid compound with a purity of ≥99%. AS1708727 is soluble in DMSO at 41.67 mg/mL. For storage, it is recommended to keep the powder at -20°C for up to 3 years or at 4°C for up to 2 years. In solvent, it can be stored at -80°C for 6 months or at -20°C for 1 month. The compound is shipped with blue ice. Pharmacokinetic properties have been studied, and AS1708727 is orally active.
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| Toxicity/Toxicokinetics |
Detailed toxicity data for AS1708727 is not provided in standard product descriptions. As a research compound, its toxicity profile has not been extensively characterized. In vivo studies have used oral doses up to 300 mg/kg in mice without reported overt toxicity. However, comprehensive toxicological studies, including acute and chronic toxicity studies, have not been reported. As with all research chemicals, standard laboratory safety precautions should be followed when handling AS1708727. Its use is limited to research applications and it is not intended for human or veterinary use.
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| References | |
| Additional Infomation |
AS1708727 is a research compound and is not approved for any clinical or therapeutic use. It is an orally active Foxo1 inhibitor that exerts anti-diabetic and anti-hypertriglyceridemic effects. AS1708727 inhibits Foxo1 with EC50 values of 0.33 µM for G6Pase and 0.59 µM for PEPCK. It reduces both blood glucose and triglyceride levels in diabetic mice at oral doses of 30 to 300 mg/kg. AS1708727 is used to study the role of Foxo1 in glucose and lipid metabolism and to explore potential treatments for diabetes and metabolic disorders. Its mechanism of action involves inhibiting Foxo1-mediated transcription of gluconeogenic genes, thereby reducing glucose production and improving lipid metabolism.
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| Molecular Formula |
C24H24CL2N2O2
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| Molecular Weight |
443.3656
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| Exact Mass |
442.121
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| CAS # |
1253226-93-5
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| PubChem CID |
49787159
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| Appearance |
White to off-white solid powder
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| LogP |
6.3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
571
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(C([H])([H])OC2=C([H])C([H])=C([H])C3C([H])=NC([H])=C([H])C2=3)=C(C([H])=C([H])C=1N(C([H])([H])[H])C(C([H])([H])C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])=O)Cl
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| InChi Key |
OZEZQEPCCWFFJQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H24Cl2N2O2/c1-28(23(29)13-16-5-2-3-6-16)21-10-9-20(25)19(24(21)26)15-30-22-8-4-7-17-14-27-12-11-18(17)22/h4,7-12,14,16H,2-3,5-6,13,15H2,1H3
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| Chemical Name |
2-cyclopentyl-N-[2,4-dichloro-3-(isoquinolin-5-yloxymethyl)phenyl]-N-methylacetamide
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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 |
| 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) |
DMSO : ~41.67 mg/mL (~93.98 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.69 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 20.8 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: 2.08 mg/mL (4.69 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: ≥ 2.08 mg/mL (4.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2555 mL | 11.2773 mL | 22.5545 mL | |
| 5 mM | 0.4511 mL | 2.2555 mL | 4.5109 mL | |
| 10 mM | 0.2255 mL | 1.1277 mL | 2.2555 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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