| Size | Price | Stock | Qty |
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| 5mg |
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| Other Sizes |
Purity: ≥98%
AZD2906 is a novel, potent and selective glucocorticoid receptor (GR) agonist which increases micronucleated immature erythrocytes in the bone marrow of rats. AZD2906 shows IC50s of 2.2, 0.3, 41.6 and 7.5 nM at GR in human, rat PBMC and human, rat whole blood, respectively. AZD2906 was found to increase the incidence of micronucleated immature erythrocytes (MIE) in the bone marrow of rats given two oral doses at the maximum tolerated level. Because GR agonists as a class are considered not to be genotoxic and AZD2906 showed no activity in the standard in vitro tests or in vivo in a rat liver comet assay, investigative studies were performed to compare AZD2906 with a reference traditional GR agonist, prednisolone. Emphasis was placed on blood and bone marrow parameters in these studies because GR activation has been reported to induce erythropoiesis which, in turn, is known to increase MIE in the bone marrow. Both compounds induced almost identical, small increases in micronucleus frequency at all doses tested. Directly comparable changes in haematological and bone marrow parameters were also seen with significant decreases in lymphoid cells in both compartments and significant increases in numbers of circulating neutrophils. Although no evidence of increased erythropoiesis was seen as increased immature erythrocyte numbers either in the blood or in the bone marrow, histopathological examination showed focal areas in the bone marrow where the erythroid population was enriched in association with an atrophic myeloid lineage. This could have been due to direct stimulation of the erythroid lineage or a secondary effect of myelosuppression inducing a rebound increase in erythropoiesis into the vacant haematopoietic cell compartment. It was concluded that the increased MIE frequencies induced by both AZD2906 and prednisolone are a consequence of their pharmacological effects on the bone marrow, either by directly inducing erythropoiesis or by some other unknown effect on cellular function, and do not indicate potential genotoxicity. This conclusion is supported by the lack of carcinogenic risk in man demonstrated by decades of clinical use of prednisolone and other GR agonists.
| Targets |
In human and rat PBMC and human and rat whole blood, AZD2906 is a selective glucocorticoid receptor (GR) with IC50 values of 2.2, 0.3, 41.6, and 7.5 nM, respectively [1].
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| ln Vitro |
In human and rat PBMC and human and rat whole blood, AZD2906 is a selective glucocorticoid receptor (GR) with IC50 values of 2.2, 0.3, 41.6, and 7.5 nM, respectively [1].
AZD2906 gave negative results in a bacterial mutation (Ames) test conducted to current ICH and OECD guidelines. AZD2906 showed no activity (negative result) in a mouse lymphoma Tk gene mutation assay performed to current ICH and OECD guidelines. AZD2906 showed no activity (negative result) in an in vitro micronucleus test using mouse lymphoma cells. Pattern of metabolites in the rat showed no structural alert for bacterial mutagenicity. The compound and its metabolites showed no evidence of forming reactive metabolites based on a quantitative whole-body autoradiography study in rats. |
| ln Vivo |
After two days of therapy, AZD2906 (5, 25, 50 mg/kg, oral) can enhance the number of micronucleated immature erythrocytes (MIE) in rat bone marrow [1]. AZD2906 (5, 25 mg/kg, oral) causes moderate to severe cortical lymphocyte atrophy in the rat thymus and causes glycogen buildup in the livers of rats [1].
Administration of AZD2906 (two oral doses, 24h apart) to male Wistar Han rats significantly increased the frequency of micronucleated immature erythrocytes (MIE) in the bone marrow at doses of 5, 25, and 50 mg/kg compared to vehicle control. The increases were statistically significant (p < 0.001) and were greater than 3-fold the concurrent control value when 6000 immature erythrocytes were scored per animal. The increased MIE frequency was observed at all dose levels with no clear dose-response, likely due to blood levels far exceeding the GR IC50. AZD2906 induced changes in haematological parameters: significant reductions in absolute reticulocyte numbers (~44-55%), total white blood cell counts (~75%), lymphocytes (~95-97%), monocytes (~75%), and eosinophils (85-100%), along with minor increases in neutrophil numbers (65-73%). In the bone marrow, flow cytometry showed reductions in total nucleated cells (6-16%) and lymphoid cells (~58-59%). Histopathological examination revealed glycogen accumulation in the liver, moderate to marked cortical lymphocytic atrophy in the thymus, and generalised mild marrow atrophy in the bone marrow with a shift in the myeloid to erythroid cell ratio, favoring erythroid lineage enrichment or retention. A rat liver comet assay using the same doses that increased bone marrow micronucleus frequency showed negative results, indicating no direct DNA damage in the liver. |
| Cell Assay |
The in vitro micronucleus test was conducted using mouse lymphoma cells, but detailed procedural steps are not provided in the main article.
The bacterial mutation test and mouse lymphoma Tk assay were performed according to current ICH and OECD guidelines. |
| Animal Protocol |
Animal/Disease Models: Male Wistar Han rat (10 weeks old) [1]
Doses: 5, 25, 50 mg/kg Route of Administration: Orally for 2 days Experimental Results: All doses caused micronucleated immature erythrocytes (MIE) after analysis With the addition of standard 2000 IE. For the bone marrow micronucleus test: Groups of seven male Wistar Han rats were given two oral doses of AZD2906 (suspended in 0.5% w/v hydroxypropyl methylcellulose and 0.1% Tween 80 in 50 mM citrate buffer, pH 4.0) at 5, 25, or 50 mg/kg, 24 hours apart. Animals were killed 24 hours after the second dose. Bone marrow was collected from a femur, and smears were prepared, stained with acridine orange, and scored for micronucleated immature erythrocytes. For haematology and histopathology investigation: Groups of eight male rats were given two oral doses of vehicle, 5, or 25 mg/kg AZD2906 and killed 24 hours after the second dose. Blood was collected for haematology analysis. One femur was taken for flow cytometric analysis of bone marrow cell populations. The other femur (attached to tibia), liver, and thymus were collected, fixed, decalcified (for bone), processed, and embedded for histopathological examination by light microscopy. |
| ADME/Pharmacokinetics |
In rats, after two oral administrations, the Cmax of AZD2906 at a dose of 5 mg/kg was 643 nmol/L, and the AUC was 7270 nmol·h/L. At a dose of 25 mg/kg, the Cmax was 2520 nmol/L, and the AUC was 36400 nmol·h/L. This compound exhibits high protein binding in both rat and human blood. Whole-body quantitative autoradiography in rats showed no radioactive retention in tissues other than the choroid and retinal pigment, indicating that the compound lacks the formation of active metabolites and has a wide distribution/elimination pathway.
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| Toxicity/Toxicokinetics |
The maximum tolerated dose (MTD) after two oral administrations in rats was 50 mg/kg. At doses of 5 and 25 mg/kg, AZD2906 induced hepatic glycogen accumulation and moderate to significant atrophy of thymic cortical lymphocytes, which are the expected pharmacological effects of glucocorticoid receptor (GR) agonists. No gross evidence of gastrointestinal damage was observed at the tested doses. Because an increase in bone marrow micronucleus frequency was observed at all tested doses, the no-observed-effect level (NOEL) for increased bone marrow micronucleus frequency was not determined in this study.
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| References | |
| Additional Infomation |
AZD2906 is a novel selective glucocorticoid receptor agonist discovered jointly by AstraZeneca and Bayer Healthcare. The observed increase in micronucleus frequency in rat bone marrow is associated with the effects of AZD2906, which is considered a result of its pharmacological action (glucocorticoid receptor agonist) and does not indicate genotoxicity or carcinogenicity. This conclusion is supported by negative results from standard in vitro genotoxicity assays, negative results from in vivo comet assays, similar effects observed with the reference GR agonist prednisolone, and a long-term clinical safety record for GR agonists (such as prednisolone). The proposed mechanism of increased MIE may involve GR-mediated erythropoiesis stimulation (direct stimulation or secondary to bone marrow suppression) or other unknown effects on bone marrow cell function, leading to an increased rate of erythroid cell division and potentially the formation of micronuclei during accelerated erythropoiesis.
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| Molecular Formula |
C26H25FN4O3
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| Molecular Weight |
460.500109434128
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| Exact Mass |
460.191
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| CAS # |
1034148-15-6
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| Related CAS # |
1034148-15-6;1034149-96-6;1034148-16-7 (1S2R isomer);
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| PubChem CID |
25013811
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
34
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| Complexity |
687
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1C=CC(=CC=1)N1C2C=CC(=CC=2C=N1)O[C@H](C1C=NC(=CC=1)OC)[C@H](C)NC(C1CC1)=O
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| InChi Key |
YDRQCGICZKAGCQ-LMKMVOKYSA-N
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| InChi Code |
InChI=1S/C26H25FN4O3/c1-16(30-26(32)17-3-4-17)25(18-5-12-24(33-2)28-14-18)34-22-10-11-23-19(13-22)15-29-31(23)21-8-6-20(27)7-9-21/h5-17,25H,3-4H2,1-2H3,(H,30,32)/t16-,25-/m0/s1
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| Chemical Name |
N-((1R,2S)-1-((1-(4-fluorophenyl)-1H-indazol-5-yl)oxy)-1-(6-methoxypyridin-3-yl)propan-2-yl)cyclopropanecarboxamide
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| Synonyms |
AZD2906; AZD-2906; AZD 2906.
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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 : ~125 mg/mL (~271.44 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.52 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 (4.52 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 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 (4.52 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 | 2.1716 mL | 10.8578 mL | 21.7155 mL | |
| 5 mM | 0.4343 mL | 2.1716 mL | 4.3431 mL | |
| 10 mM | 0.2172 mL | 1.0858 mL | 2.1716 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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