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Purity: ≥98%
AZD2858 is a novel, potent, orally bioactive, and selective GSK-3 (glycogen synthase kinase-3) inhibitor with the potential to be used in fracture healing. It inhibits GSK-3 with an IC50 of 68 nM. It can increase bone mass in rats and activate the Wnt signaling. After a two-week treatment period, treatment rats given AZD2858 orally experienced a dose-dependent increase in trabecular bone mass. Cortical sites also noticed the notable effect. In biomechanical testing, the diaphyseal strength of femora and the vertebral compression strength both increased.
| Targets |
GSK-3α (IC50 = 0.9 nM); GSK-3β (IC50 = 5 nM); CDK5/p25 (IC50 = 356 nM); Haspin (IC50 = 366 nM); CDK5/p35 (IC50 = 387 nM); DYRK2 (IC50 = 491 nM); CDK2/cyclin A (IC50 = 810 nM); CDK1/cyclin B (IC50 = 1246 nM); PIM3 (IC50 = 1269 nM); TLK2 (IC50 = 1381 nM); PKD2 (IC50 = 2462 nM); CDK2/cyclin E (IC50 = 3310 nM); Aurora-A (IC50 = 4966 nM)
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| ln Vitro |
AZD2858 is a selective GSK-3 inhibitor with an IC50 of 68 nM, inhibits tau phosphorylation at the S396 site, activates Wnt signaling pathway. A 3-fold increase in -β-cateninlevels is seen in primary isolated human osteoblast-like cells after AZD2858 treatment (1 μM, 12 h). [1] In vitro, AZD2858 stimulates hADSC commitment to osteoblasts and osteogenic mineralization while causing -β-cateninto stabilize in human and rat mesenchymal stem cells. [2]
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| ln Vivo |
After two weeks of treatment, oral AZD2858 treatment in rats results in a dose-dependent increase in trabecular bone mass compared to control, with the maximum effect occurring at a dose of 20 mg/kg once daily (total BMC: 172% of control). Cortical sites exhibit a minor but noteworthy effect (total BMC: 111% of control).[1] AZD285 treatment (30 μmol/kg) on rats daily for up to 3 weeks shows an increase in both mineral density (of 28% at 2 weeks and 38% at 3 weeks) and mineral content (of 81% at 2 weeks and 93% at 3 weeks) in the calluses. AZD285 treatment makes the fractures heals more rapidly, with a bony callus without an obvious endochondral component.[3] Over the course of a 28-day exposure period, rats exposed to AZD2858 exhibit time-dependent changes in serum biomarkers of bone turnover and an increase in bone mass. Following 7 days, AZD2858 increases the bone formation biomarker P1NP and decreases the bone resorption biomarker TRAcP-5b in rats, indicating increased bone anabolism and decreased resorption.[2]
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| Enzyme Assay |
In vitro functional activity of AZD2858 is evaluated using NIH-3T3 cells that express 4-repeat Tau. In 6-well plates, the cells are plated at a density of 6 105 cells/well after being grown in DMEM media with 2 mM L-glut and 10% HiFCS. At concentrations of 1, 10, 100, 500, 1000, 2000, and 10,000 nM, AZD2858 is dosed in triplicates in each experiment. A 100 L volume of ice-cold lysis buffer containing 0.5% NP-40, 10 mM Tris, pH 7.2, 150 mM NaCl, and 2 mM EDTA is used to treat cells for 4 hours prior to cell lysis. Cocktail Protease Inhibitors, 50 mM NaF, 0.2 mM NaVO4, and other phosphatase and protease inhibitors are added to a suspension to create a reaction. After the solution has been snap frozen at 80 °C for at least one hour, it is thawed on ice, the lysate is clarified using centrifugation, and then a Western blot is performed in accordance with industry standards. After blocking, the blots are exposed overnight to the primary antibody, Phospho-Ser396-tau (1:1000), washed, and then incubated with the secondary antibody (donkey anti-rabbit, 1:5000). Re-probing is done using the secondary horseradish peroxidase linked antibody (sheep anti-mouse, 1:10000) and the primary antibody Tau5 (1:200). The ratio of S396 tau to total tau (tau5) is calculated after all blots have been quantified using densitometric analysis and developed using ECL Western blot detection reagents and Kodak X-ray films.
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| Cell Assay |
Rat MSCs (isolated from Sprague Dawley rat bone marrow at less than 8 weeks after gestation) and human adipose derived stem cells (HADSCs) are cultured in DMEM with 5% FBS and 2 mM GlutaMax as the basal medium. Before being treated with AZD2858 (0.3 nM to 20 mM), cells are seeded in 96-well plates with basal media (3–5000 cells/well) for 18 hours. -Catenin stabilization is assessed after 24 hours.
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| Animal Protocol |
Each rat is dosed orally with vehicle or AZD2858 using a plastic gavage tube. The dosage is 10 mL/kg. Deionized water that has been pH-adjusted to 3.50.1 makes up the vehicle. pH 3.50.1 is adjusted for formulations. The doses are 0, 0.2, 2, or 20 mg/kg administered either twice daily (TD), once daily (OD), every other day (O/2D), or every fourth day (O/4D) for a total of 14 days. The protocol yields 13 groups with an average of 8 animals each (104 animals total). Each animal receives a subcutaneous injection of a bicarbonate buffered calcein solution (8 mg/kg, 1 mL/kg)[1] at 7 days following the study's start and once more 2 days before the planned terminal necropsy.
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| References |
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| Additional Infomation |
AZD2858 is a member of the class of pyrazines that is pyrazine substituted by (pyridin-3-yl)aminocarbonyl, amino, and 4-(4-methylpiperazine-1-sulfonyl)phenyl groups at positions 2, 3 and 6, respectively. It is a potent inhibitor of GSK3alpha and GSK3beta (IC50 values of 0.9 and 4.9 nM, respectively) and increases bone mass (via Wnt activation) in rats. It has a role as an EC 2.7.11.26 (tau-protein kinase) inhibitor, an antineoplastic agent, a bone density conservation agent and a Wnt signalling activator. It is a member of pyrazines, a secondary carboxamide, a member of pyridines, a N-methylpiperazine, a sulfonamide and an aromatic amine.
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| Molecular Formula |
C21H23N7O3S
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|---|---|
| Molecular Weight |
453.5174
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| Exact Mass |
453.158
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| Elemental Analysis |
C, 55.62; H, 5.11; N, 21.62; O, 10.58; S, 7.07
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| CAS # |
486424-20-8
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| Related CAS # |
2108876-05-5 (HCl);486424-21-9 (xHCl);486424-20-8;
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| PubChem CID |
10138980
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| Appearance |
Green to khaki solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.663
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| LogP |
2.97
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
730
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1C([H])=C([H])C(C2=C([H])N=C(C(C(N([H])C3=C([H])N=C([H])C([H])=C3[H])=O)=N2)N([H])[H])=C([H])C=1[H])(N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])(=O)=O
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| InChi Key |
FHCSBLWRGCOVPT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H23N7O3S/c1-27-9-11-28(12-10-27)32(30,31)17-6-4-15(5-7-17)18-14-24-20(22)19(26-18)21(29)25-16-3-2-8-23-13-16/h2-8,13-14H,9-12H2,1H3,(H2,22,24)(H,25,29)
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| Chemical Name |
3-amino-6-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]-N-3-pyridinyl-2-pyrazinecarboxamid
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| Synonyms |
AZD-2858; AZD2858; AZD 2858
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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: ~7 mg/mL (15.43 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 1.25 mg/mL (2.76 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 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: ≥ 1.25 mg/mL (2.76 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 12.5 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: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2050 mL | 11.0249 mL | 22.0497 mL | |
| 5 mM | 0.4410 mL | 2.2050 mL | 4.4099 mL | |
| 10 mM | 0.2205 mL | 1.1025 mL | 2.2050 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.
Expression of TAZ and Osterix, markers of commitment to osteoblastogenesis in human ADSC. Toxicol Appl Pharmacol. 2013 Oct 15;272(2):399-407 |
Time course of serum bone turnover biomarkers and femur histopathology changes with AZD2858 dosed orally for 3, 7, 14, 21 or 28 days |
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