AZD2906
目录号 : GC32585
AZD2906为一种选择性的糖皮质激素受体glucocorticoidreceptor(GR)激动剂，对人、大鼠PBMC和全血中GR的IC50值分别为2.2，0.3，41.6和7.5nM。AZD2906能够增加大鼠骨髓中的微核未成熟红细胞。
Cas No.:1034148-15-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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- SDS (Safety Data Sheet)
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AZD2906 is a selective glucocorticoid receptor (GR) agonist, with 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 increases micronucleated immature erythrocytes (MIE) in the bone marrow of rats[1].
AZD2906 is a selective glucocorticoid receptor (GR), with IC50s of 2.2, 0.3, 41.6 and 7.5 nM at GR in human, rat PBMC and human, rat whole blood, respectively[1].
AZD2906 (5, 25, 50 mg/kg, p.o.) increases micronucleated immature erythrocytes (MIE) in the bone marrow of rats after treatment for 2 days[1].AZD2906 (5, 25 mg/kg, p.o.) induces an accumulation of glycogen in the liver of rats, and exhibits cortical lymphocytic atrophy of a moderate to marked degree in the thymus of rats[1].|| Animal Model:|Male Wistar Han rats (10 weeks old)[1]|Dosage:|5, 25, 50 mg/kg|Administration:|P.O. for 2 days|Result:|Caused significant increases in micronucleated immature erythrocytes (MIE) at all doses after analysis of the standard 2000 IE.
[1]. Hayes JE, et al. Micronucleus induction in the bone marrow of rats by pharmacological mechanisms. I: glucocorticoid receptor agonism. Mutagenesis. 2013 Mar;28(2):227-32.
| Cas No. | 1034148-15-6 | SDF | |
| Canonical SMILES | FC1=CC=C(N2N=CC3=CC(O[C@@H]([C@@H](NC(C4CC4)=O)C)C5=CC=C(N=C5)OC)=CC=C23)C=C1 | ||
| 分子式 | C26H25FN4O3 | 分子量 | 460.5 |
| 溶解度 | DMSO : 125 mg/mL (271.44 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Molecular View on the Dissociation Pathways and Transactivation Regulation Mechanism of Nonsteroidal GR Ligands
J Chem Inf Model 2022 Nov 14;62(21):5233-5245.PMID:34506144DOI:10.1021/acs.jcim.1c00150.
As a major drug target for anti-inflammatory therapy, the glucocorticoid receptor (GR) regulates a wide range of physiological processes through transactivation (TA) or transrepression. GR TA is involved in many adverse effects of GR-targeting drugs, and therefore, the discovery of novel GR ligands with lower TA activity and longer residence time is quite urgent. Undoubtedly, understanding the ligand dissociation mechanisms and the structural basis of the TA regulation is crucial for the development of novel GR-targeting drugs. Here, we used random accelerated molecular dynamics (RAMD) and funnel metadynamics (FM) simulations to explore the dissociation mechanisms of 5 classic glucocorticoids and 6 nonsteroidal GR ligands. Multiple ligand dissociation pathways were discovered. The classic glucocorticoids exhibit a strong preference for Path I, and most nonsteroidal ligands tend to dissociate along mixed pathways. We also find that the distinct unbinding preferences for AZD2906 and AZD9567, two representative nonsteroidal ligands with similar scaffolds but different TA activities, are primarily determined by their different polar interactions with the surrounding residues. Notably, the binding of AZD9567 poses a substantial impact on the conformation of the GR homodimer interface, which provides a valuable clue to understand the mechanisms of the TA-related side effects induced by the adjustments of the homodimerization process. These findings are critical for the structure-based rational design of novel GR ligands with more potent anti-inflammatory potency and reduced side effects.
Micronucleus induction in the bone marrow of rats by pharmacological mechanisms. I: glucocorticoid receptor agonism
Mutagenesis 2013 Mar;28(2):227-32.PMID:23340811DOI:10.1093/mutage/ges076.
A novel selective glucocorticoid receptor (GR) agonist, 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.
A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation
Sci Rep 2018 Aug 27;8(1):12894.PMID:30150712DOI:10.1038/s41598-018-31150-w.
It has been suggested that glucocorticoid receptor (GR) agonists that promote GR homodimerization more than standard glucocorticoids such as Dexamethasone could be more effective anti-inflammatory molecules against acute and life-threatening inflammatory conditions. To test this hypothesis, we set up a screening pipeline aimed at discovering such Selective Dimerizing GR Agonists and Modulators (SEDIGRAM). The pipeline consists of a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE). This assay represents GR dimerization in human A549 lung epithelial cells. In the pipeline, this is followed by analysis of endogenous GRE-driven gene expression, a FRET assay confirming dimerization, and monitoring of in vitro and in vivo anti-inflammatory activity. In a proof of principle experiment, starting from seven candidate compounds, we identified two potentially interesting compounds (Cortivazol and AZD2906) that confer strong protection in a mouse model of aggressive TNF-induced lethal inflammation. A screening pipeline for SEDIGRAM may assist the search for compounds that promote GR dimerization and limit overwhelming acute inflammatory responses.