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INCB3344

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Catalog No.
A3494
CCR2趋化因子受体拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 3,250.00
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5mg
¥ 2,560.00
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10mg
¥ 3,360.00
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50mg
¥ 9,060.00
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100mg
¥ 14,020.00
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Background

INCB3344 is a novel potent and selective antagonist of CCR2 receptor, which possesses an IC 50 of 10 nM for CCL2. [1]

CCR2 is a chemokine receptor mainly expressed on monocytes which acts as the key receptor in mediating their tissue influx in the context of immune-based inflammation. CCR2 is a G protein-coupled receptor (GPCR), whose ligands include the chemokines MCP family, including CCL2, CCL7, CCL8. These ligands bind CCR2 receptor with high affinity and elicit a chemotactic signal which leads to directed migration of the receptor-bearing cells. CCL2 has been shown to be relevant in high concentrations in various inflammatory lesions, implicating this chemokine as a physiologically important chemotactic signal for monocytes. [1]

Characterization of the pharmacological activity of INCB3344 was first evaluated by testing its ability to inhibit CCL2 binding to CCR2 in a whole cell binding assay using a murine monocyte cell line, WEHI-274.1 and 125I-labeled mCCL2 as a tracer. The binding IC 50 of INCB3344 in this assay was determined to be 10±5 nM, and inhibition greater than 90% binding was observed at a concentration of 90nM . The chemotaxis inhibitory activity of different concentrations of INCB3344 was evaluated using 30nM mCCL2 as the agonist. The result showed a similar potency to the binding assay. Selectivity of INCB3344 was evaluated against a panel of GPCRs including several human chemokine receptors using radioligand binding assays. Results from these studies demonstrate at least 100-fold selectivity of INCB3344 against all of the receptors tested. [1]

INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse delayed-type hypersensitivity model. The histopathological analysis of tissues from the delayed-type hypersensitivity model illustrates that inhibitory activity of CCR2 leads to a substantial reduction in tissue inflammation. [1]

Reference:
[1].  Brodmerkel C M, Huber R, Covington M, et al. Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344[J]. The Journal of Immunology, 2005, 175(8): 5370-5378.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt577.24
Cas No.1262238-11-8
FormulaC29H34F3N3O6
SynonymsINCB 3344; INCB-3344
Solubility≥25.9 mg/mL in DMSO, ≥89.8 mg/mL in EtOH, <2.365 mg/mL in H2O
Chemical NameN-[2-[[(3S,4S)-1-[4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-4-ethoxypyrrolidin-3-yl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide
SDFDownload SDF
Canonical SMILESCCOC1CN(CC1NC(=O)CNC(=O)C2=CC(=CC=C2)C(F)(F)F)C3CCC(CC3)(C4=CC5=C(C=C4)OCO5)O
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

结合实验

使用鼠单核细胞系WEHI 274.1细胞进行全细胞结合测定。将用RPMI 1640配置的不同浓度的INCB3344加入到RPMI 1640、0.1% BSA、20 mM HEPES培养的细胞(5×105)中,然后立即加入150 pM 125I-标记的mCCL2(小鼠CCL2(JE)中,室温孵育30分钟。在非特异性对照组加入0.3 μM mCCL2代替INCB3344。然后通过1.2-μm聚偏二氟乙烯过滤器收集细胞,风干滤膜,通过在γ计数器中计数测定结合。研究表明,拮抗剂活性被定义为特异性结合的IC50所需的抑制剂浓度。将总结合减去非特异性结合定义为特异性结合,通常占总结合的97%。

细胞实验[1]:

细胞系

WEHI-274.1细胞

溶解方法

溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月

反应条件

0.3-300 nM;6 min

实验结果

在WEHI-274.1细胞中,使用30 nM mCCL2作为激动剂,INCB3344抑制单核细胞趋化性,IC50值为10 nM。INCB3344阻断响应于mCCL2的ERK磷酸化,IC50值为3-10 nM,这是由CCR2信号传导所介导的。

动物实验 [1]:

动物模型

腹膜内注射巯基乙酸盐的雌性BALB/c小鼠(20 g)

剂量

30、60或100 mg/kg BID;48 h;口服

实验结果

INCB3344以剂量依赖性的方式减少灌洗液中的总细胞数目,30mg/kg、60 mg/kg和100 mg/kg浓度分别抑制36%、55%和73%的单核细胞流入。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. Brodmerkel CM, Huber R, Covington M, et al. Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344[J]. The Journal of Immunology, 2005, 175(8): 5370-5378.

质量控制

化学结构

INCB3344