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| 25mg |
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Purity: ≥98%
AZD1080 is a selective, potent, orally bioactive, and brain permeable GSK3 (glycogen synthase kinase-3) inhibitor with neuroprotective effects. With Ki of 6.9 nM and 31 nM, respectively, it inhibits human GSK3 and GSK3 while also showing >14-fold selectivity for GSK3 over CDK2, CDK5, CDK1, and Erk2. By interacting with GSK3 and binding to the ATP pocket, AZD1080 has been shown to inhibit it, according to the high resolution X-ray crystal structure. Additionally, recombinant human GSK3 and GSK3 have been shown to be suppressed by AZD1080, with Ki values of 6.9 nM and 31 nM, respectively. In intact rat brain and cells expressing human tau, AZD1080 prevents tau phosphorylation.
| Targets |
GSK-3α (pKi = 8.2 nM); GSK-3β (pKi = 7.5 nM); cdk5 (pKi = 6.4 nM); cdk2 (pKi = 5.9 nM); cdk1 (pKi = 5.7 nM)
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| ln Vitro |
AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3 with a Ki of 6.9 nM and 31 nM, respectively. It also exhibits >14-fold selectivity against cdk2, cdk5, cdk1, and Erk2. With an IC50 of 324 nM, AZD1080 prevents tau phosphorylation in cells that express human tau. [1]
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| ln Vivo |
AZD1080 inhibits tau phosphorylation in rat brain after oral dministration, with a brain/plasma exposure ratio of 0.5 to 0.8 at peak concentrations. In mice, AZD1080 restores cognitive deficits and heals damaged synapses. Acute oral administration of AZD1080 reduces the ratio of phosphorylated to total glycogen synthase (GS) in a dose-dependent manner, with a mean maximal inhibitory effect of 49% at the highest dose (10 μmol/kg) at 2 hours after dosing. [1]
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| Enzyme Assay |
The GSK3β, Cdk2, and Cdk5 Ki’s are determined using scintillation proximity assays and kinetic analyses. The GSK3α assay is conducted as part of the GSK3α assay. For the purpose of determining the Ki value for GSKα , the KM value of ATP is 10 M. Cdk1 is inhibited in this process. To determine the Ki value, 51 M of ATP is used as the KM value. An Erk2 SPA kit, p42 MAPK kinase (20 U/well), and biotinylated MBP are used to measure Erk2 activity. In order to determine the Ki value, the KM value of ATP is 71 μM[1].
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| Cell Assay |
The four-repeat tau protein is engineered to express consistently in 3T3 fibroblasts. These cells have high endogenous concentrations of GSK3, which can constitutively phosphorylate tau protein. LiCl prevents this phosphorylation from occurring. Cultures are twice washed with 5 mM MgCl2-PBS after treatment with various chemicals. Extracts for Western blot analysis are prepared by homogenizing cells in ice-cold extraction buffer consisting of 20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM NaF, 1% Triton X-100, 1 mM sodium orthovanadate, 10 mM EDTA, and protease inhibitors (2 mM phenylmethylsulfonyl fluoride, 10 μg/ml aprotinin, 10 μg/ml leupeptin, and 10 μg/ml pepstatin). The samples are homogenized at 4 °C, and the Bradford method is used to calculate the protein content. On a 10% SDS-PAGE gel, the total protein (25 μg) is electrophoresed before being transferred to a nitrocellulose membrane. The primary antibodies tau Ser(P)-396, tau5, and anti-GSK3β are used in the experiments at a 1:1000 dilution each. At 4 °C overnight, the filters are incubated with the antibody in 5% nonfat dried milk. For immunodetection, a secondary antibody (1:5000) is used, then ECL detection tools. Densitometric scanning is used to measure immunoreactivity.
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| Animal Protocol |
Mice: A total of 161 male C57BL/6 mice between the ages of 8 and 12 weeks are used. The animals are housed in standard cages with three to five mice each, and they are given regular rodent chew and unlimited access to tap water. Each experimental group typically consists of 9–12 mice, with 2-4 mice in the satellite groups (see below for information on determining compound exposure in plasma and the brain). Acute or subchronic (twice daily for 3 days) oral gavage administration of AZD1080 (4.0 or 15 μmol/kg) or vehicle (water with 0.5% ascorbic acid, 0.01% EDTA, pH 2.0) is done. After the final AZD1080 administration, the training trial is conducted 1.5, 3, or 5 hours later.
Rats: The rats used are 71 adult male Sprague-Dawley rats (250-300 g). The rats are given an acute dose of AZD1080 (1, 3 or 10 mol/kg) or a vehicle (5 mL/kg) of water with 0.5% ascorbic acid, 0.01% EDTA, and pH 2.0. After administration, the rats are sedated and blood from the abdominal aorta is collected in heparin microtainer tubes at 1, 2, 3, 6, or 24 hours. Blood samples are used to isolate peripheral blood mononuclear cells (PBMC). To process the plasma and conduct the subsequent bioanalysis, separate blood samples are obtained. |
| References | |
| Additional Infomation |
AZD1080 is a member of the class of hydroxyindoles that is 1H-indole substituted by hydroxy, 5-(morpholin-4-ylmethyl)pyridin-2-yl, and cyano groups at positions 2, 3 and 5, respectively. It is a potent, brain permeable inhibitor of human GSK3alpha and GSK3beta with Ki of 6.9 nM and 31 nM, respectively. The drug was being developed by AstraZeneca for the treatment of Alzheimer's disease (clinical trial now discontinued). It has a role as an EC 2.7.11.26 (tau-protein kinase) inhibitor, a tau aggregation inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of morpholines, a member of pyridines, a member of hydroxyindoles, a nitrile and a tertiary amino compound.
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| Molecular Formula |
C19H18N4O2
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|---|---|
| Molecular Weight |
334.3718
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| Exact Mass |
334.142
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| Elemental Analysis |
C, 68.25; H, 5.43; N, 16.76; O, 9.57
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| CAS # |
612487-72-6
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| Related CAS # |
612487-72-6
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| PubChem CID |
135564570
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| Appearance |
Orange solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
594.0±50.0 °C at 760 mmHg
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| Flash Point |
313.0±30.1 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.716
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| LogP |
1.36
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
25
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| Complexity |
501
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O1C([H])([H])C([H])([H])N(C([H])([H])C2=C([H])N=C(C([H])=C2[H])C2=C(N([H])C3C([H])=C([H])C(C#N)=C([H])C2=3)O[H])C([H])([H])C1([H])[H]
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| InChi Key |
JULOXTBHCHEFBE-ZCXUNETKSA-N
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| InChi Code |
InChI=1S/C19H18N4O2/c20-10-13-1-3-16-15(9-13)18(19(24)22-16)17-4-2-14(11-21-17)12-23-5-7-25-8-6-23/h1-4,9,11,21H,5-8,12H2,(H,22,24)/b18-17-
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| Chemical Name |
(Z)-3-(5-(morpholinomethyl)pyridin-2(1H)-ylidene)-2-oxoindoline-5-carbonitrile
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| Synonyms |
AZD-1080;AZD-1080; AZD 1080
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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: ~52 mg/mL (155.5 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.48 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 (7.48 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: 30% PEG400+0.5% Tween80+5% propylene glycol: 20 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9907 mL | 14.9535 mL | 29.9070 mL | |
| 5 mM | 0.5981 mL | 2.9907 mL | 5.9814 mL | |
| 10 mM | 0.2991 mL | 1.4953 mL | 2.9907 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.
Binding, potency, and selectivity of AZD1080. J Neurochem. 2013 May;125(3):446-56 |
AZD1080 reverses MK-801-induced impairments in mouse model of cognition |
Demonstration of peripheral target engagement in rats and in human |
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