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MK 0893

现货
Catalog No.
A3608
胰高血糖素受体/ IGF-1R拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 4,100.00
现货
5mg
¥ 3,150.00
现货
10mg
¥ 5,700.00
现货
50mg
¥ 14,250.00
Ship with 10-15 days

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Background

MK 0893 is an inhibitor of both glucagon receptor and IGF-1R with IC50 values of 6.6nM and 6nM, respectively [1, 2].

In a receptor binding assay using a membrane preparation from a CHO cell line expressing the human GCGR, MK 0893 is shown to inhibit the bing between glucagon and the GCGR(IC50 value of 6.6 ± 3.5nM) and subsequently induce cAMP production(IC50 value of 15.7 ± 5.4nM). MK 0893 is proved to be a competitive, reversible GCGR antagonist, as evidenced by Schild Analysis in this cell line. And in an acute glucagon challenge model in hGCGR mice, MK 0893 is found to be active in blunting glucagon-induced glucose excursion. All these effects make MK 0893 be a potential oral treatment for type 2 diabetes. Additionally, MK 0893 is also reported as a potent, selective, and orally bioavailable IGF-1R inhibitor with robust in vivo efficacy in an IGF-driven mouse xenograft model. [1, 2].

References:
[1] Yusheng Xiong, Jian Guo, Mari R. Candelore, Rui Liang, Corey Miller, Qing Dallas-Yang, Guoqiang Jiang, Peggy E. McCann, Sajjad A. Qureshi, Xinchun Tong, Shiyao Sherrie Xu, Jackie Shang, Stella H. Vincent, Laurie M. Tota, Michael J. Wright, Xiaodong Yang, Bei B. Zhang, James R. Tata, and Emma R. Parmee. Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes. Journal of Medicinal Chemistry. 2012, 55: 6137-6148.
[2] Meizhong Jin, Andrew Kleinberg, Andy Cooke, Prafulla C. Gokhale, Kenneth Foreman, Hanqing Dong, Kam W. Siu, Mark A. Bittner, Kristen M. Mulvihill, Yan Yao, Darla Landfair, Matthew O’Connor, Gilda Mak, Jonathan A. Pachter, Robert Wild, Maryland Rosenfeld-Franklin, Qunsheng Ji, Mark J. Mulvihill. Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy. Bioorganic & Medicinal Chemistry Letters. 2011, 21: 1176–1180.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt587.14
Cas No.870823-12-4
FormulaC32H27Cl2N3O4
SynonymsMK0893; MK-0893
Solubility≥24.05 mg/mL in DMSO, ≥4.8 mg/mL in EtOH with ultrasonic and warming, <2.07 mg/mL in H2O
Chemical Name3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid
SDFDownload SDF
Canonical SMILESCC(C1=CC=C(C=C1)C(=O)NCCC(=O)O)N2C(=CC(=N2)C3=CC(=CC(=C3)Cl)Cl)C4=CC5=C(C=C4)C=C(C=C5)OC
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Chicchi等之前阐述的方法维持表达人胰高血糖素受体(CHO hGCGR)的CHO细胞系并制备细胞膜。将2-5 μg细胞膜加入含有50 mMTris、pH7.5、5 mM MgCl2、2 mM EDTA、1%牛血清白蛋白、12%甘油、0.2mg小麦胚凝集素包被的聚乙烯甲苯闪光距离测定珠,与MK 0893(100% DMSO溶解MK 0893,2.5%的终浓度)以及50 pM 125I-胰高血糖素孵育,室温下温育3小时,并用Wallac-Microbeta计数器测量总结合放射性。使用1μM未标记的胰高血糖素测定非特异性计数。使用非线性回归分析软件GraphPad Prismv4分析数据。

细胞实验[1]:

细胞系

表达hGCGR的CHO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

56-1000 nM;30 min.

实验结果

在表达hGCR的CHO细胞中,MK 0893剂量依赖性地使胰高血糖素的EC50右移,不改变胰高血糖素的最大效应。MK 0893抑制cAMP产生。

动物实验[1]:

动物模型

hGCGRob/ob小鼠

剂量

3、10和30 mpk;1 h;口服

实验结果

3、10和30 mpk的MK 0893分别将胰高血糖素(15 μg/kg)刺激的葡萄糖升高降低30%、56%和81%。

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]. Xiong Y, Guo J, Candelore MR, et al. Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes. J Med Chem, 2012, 55(13): 6137-6148.

生物活性

描述 MK 0893是胰高血糖素受体(glucagon receptor)和IGF-1R的抑制剂,IC50值分别为6.6 nM和6 nM。
靶点 glucagon receptor IGF-1R        
IC50 6.6 nM 6 nM        

质量控制

化学结构

MK 0893

相关生物数据

MK 0893