| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Glucokinase (GK), also known as hexokinase IV. AR453588 hydrochloride allosterically activates glucokinase with an EC50 of 42 nM, enhancing glucose metabolism in pancreatic β-cells and hepatocytes.
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| ln Vitro |
AR453588 hydrochloride is a potent glucokinase activator with an EC50 of 42 nM. It enhances glucose-stimulated insulin secretion in pancreatic β-cells and increases glucose uptake and glycogen synthesis in hepatocytes. The compound shows anti-hyperglycemic activity in cell-based assays and has been validated in both normal and diabetic rodent models. AR453588 hydrochloride exhibits 23% AUCglucose reduction at 10 mg/kg in a mouse oral glucose tolerance test, exceeding the effect of sitagliptin at 30 mg/kg.
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| ln Vivo |
In normal C57BL/6J mice, oral AR453588 hydrochloride (3–30 mg/kg) lowers postprandial blood glucose [1]. In ob/ob mice, AR453588 hydrochloride (3–30 mg/kg; oral; once daily for 14 days) showed anti-hyperglycemic activity over the course of the 14-day dose range [1]. Following treatment with 10 mg/kg of AR453588 hydrochloride po, Tmax, AUCinf, Vss, Cmax, and F were, respectively, 1.0 mL/min/kg, 4.65 h μg/mL, 1.67 μg/mL, and 60.3% [1]. CL, AUCinf, Vss, and t1/2 of 21.6 mL/min/kg, 0.77 hμg/mL, 0.746 L/kg, and 1.28 hours, respectively, were observed with AR453588 hydrochloride (1 mg/kg; iv) treatment [1].
AR453588 hydrochloride (3-30 mg/kg, p.o.) lowers post-prandial glucose in normal C57BL/6J mice and exhibits anti-hyperglycemic activity in a dose-ranging 14-day ob/ob mouse study without causing hypoglycemia at 10 mg/kg. Following oral administration at 10 mg/kg in male CD-1 mice, the Tmax, AUCinf, Vss, Cmax, and F are 1.0 h, 4.65 h·μg/mL, 1.67 μg/mL, and 60.3%, respectively. Intravenous administration at 1 mg/kg yields a CL of 21.6 mL/min/kg and a t1/2 of 1.28 hours. |
| Enzyme Assay |
The glucokinase activity assay is performed in a cell-free system using recombinant human glucokinase. The assay buffer typically contains Tris-HCl (pH 7.5 or 9.0), MgCl₂, KCl, and DTT. Glucose, ATP, and NADP⁺ are added as substrates, and glucose-6-phosphate dehydrogenase (G6PDH) is included as a coupling enzyme. Test compounds are serially diluted in DMSO and added to the reaction mixture. The production of NADPH is monitored spectrophotometrically at 340 nm or fluorometrically using a fluorescent probe such as resorufin. The EC50 value is calculated from the dose-response curve.
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| Cell Assay |
Cell-based assays for glucokinase activation use pancreatic β-cell lines (e.g., INS-1, MIN6) or primary hepatocytes. Cells are treated with various concentrations of AR453588 hydrochloride or vehicle for 30-60 minutes. A positive control group with insulin (100 nM) is included. Glucose uptake is initiated by adding KRH buffer containing 2-deoxy-D-[³H]-glucose and incubated for 5-10 minutes at 37°C. Uptake is terminated by washing with ice-cold PBS. Cells are lysed, and radioactivity is measured by scintillation counting. Data are normalized to protein concentration.
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| Animal Protocol |
Animal/Disease Models: Male diabetic ob/ob mice [1]
Doses: 3, 10, 30 mg/kg Route of Administration: Orally, one time/day for 14 days Experimental Results: diminished fasting blood glucose and AUC OGTT in control animals on day 14 (Oral Glucose Tolerance Test). Animal/Disease Models: Male CD-1 mice [1] Doses: 10 mg/kg Route of Administration: po (pharmacokinetic/PK/PK analysis) Experimental Results: Tmax, AUCinf, Vss, Cmax and F were 1.0 mL/min/kg, respectively. 4.65 h μg/mL, respectively 1.67 μg/mL and 60.3% In vivo efficacy is evaluated in male diabetic ob/ob mice and normal C57BL/6J mice. AR453588 hydrochloride is administered orally at doses of 3, 10, or 30 mg/kg once daily for 14 days. For oral glucose tolerance tests (OGTT), mice are fasted for 6 hours, and a baseline blood sample is collected. The compound is administered via oral gavage, and after 30-60 minutes, a glucose solution (2 g/kg) is administered orally. Blood glucose levels are measured at 15, 30, 60, 90, and 120 minutes after glucose challenge. The AUC is calculated to quantify glucose excursion. Pharmacokinetic parameters are determined in male CD-1 mice following oral (10 mg/kg) and intravenous (1 mg/kg) administration by measuring plasma concentrations using LC-MS/MS. |
| References |
| Molecular Formula |
C25H26CLN7O2S2
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|---|---|
| Molecular Weight |
556.10
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| Exact Mass |
555.127
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| CAS # |
1065606-97-4
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| Related CAS # |
AR453588;1065609-00-8
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| PubChem CID |
67488085
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
714
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(C=CC=N1)OC2=C(N=CC(=C2)SC3=CC=CC=N3)NC4=NC(=NS4)C5CCN(CC5)C(=O)C.Cl
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| InChi Key |
DVXDJNBGXCILIU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H25N7O2S2.ClH/c1-16-20(6-5-11-26-16)34-21-14-19(35-22-7-3-4-10-27-22)15-28-24(21)30-25-29-23(31-36-25)18-8-12-32(13-9-18)17(2)33;/h3-7,10-11,14-15,18H,8-9,12-13H2,1-2H3,(H,28,29,30,31);1H
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| Chemical Name |
1-[4-[5-[[3-(2-methylpyridin-3-yl)oxy-5-pyridin-2-ylsulfanylpyridin-2-yl]amino]-1,2,4-thiadiazol-3-yl]piperidin-1-yl]ethanone;hydrochloride
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| Synonyms |
AR453588 HCl; AR-453588 HCl
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7982 mL | 8.9912 mL | 17.9824 mL | |
| 5 mM | 0.3596 mL | 1.7982 mL | 3.5965 mL | |
| 10 mM | 0.1798 mL | 0.8991 mL | 1.7982 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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