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  • MK 0893
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MK 0893

MK 0893 是一种有效的选择性胰高血糖素受体拮抗剂,IC50 为 6.6 nM,对 GIPR、PAC1、GLP-1R、VPAC1 和 VPAC2 的选择性 > 200 倍。

原价
¥3425-14150
价格
2740-11320
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  • 货号: ajci13828
  • CAS: 870823-12-4
  • 别名: N-[4-[(1S)-1-[3-(3,5-二氯苯基)-5-(6-甲氧基-2-萘基)-1H-吡唑-1-基]乙基]苯甲酰]-BETA-丙氨酸,MK0893; MK-0893
  • 分子式: C32H27Cl2N3O4
  • 分子量: 588.48
  • 纯度: >98%
  • 溶解度: ≥ 24.05 mg/mL in DMSO, ≥ 4.8 mg/mL in EtOH with ultrasonic and warming
  • 储存: Store at -20°C
  • 库存: 现货

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].

参考文献:
[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.

Protocol

Kinase experiment [1]:

Binding assays

A CHO cell line expressing the human glucagon receptor (CHO hGCGR) was maintained and membranesprepared as described in Chicchi et al. Membranes (2-5 μg) were incubated in buffer containing 50 mM Tris, pH 7.5, 5 mM MgCl2, 2 mM EDTA, 1% bovine serum albumin, 12% glycerol, 0.2 mg of wheat germ agglutinin-coated polyvinyltoluene scintillation proximity assay beads, increasing concentration of MK 0893 (diluted in 100% DMSO and added to the assay at a final concentration of 2.5%), and 50 pM 125I-glucagon. The assay was incubated for 3 h at room temperature, and the total bound radioactivity was measured with a Wallac-Microbeta counter. Nonspecific counts were determined using 1 μM unlabeled glucagon. Data were analyzed using the nonlinear regression analysis software GraphPad Prism, v4.

Cell experiment [1]:

Cell lines

CHO cells expressing the hGCGR.

Preparation method

Dissolved in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

56-1000 nM; 30 min.

Applications

In CHO cells expressing the hGCGR, MK 0893 dose dependently rightshifts the EC50 of glucagon without changing the maximum effect of glucagon. MK 0893 inhibits cAMP production.

Animal experiment [1]:

Animal models

hGCGR ob/ob mice.

Dosage form

3, 10, and 30 mpk;1 h; administrated orally.

Applications

MK 0893 reduces glucose elevation stimulated by glucagon (15 μg/kg) by 30%, 56%, and 81% at 3, 10, and 30 mpk, respectively.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

参考文献:

[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.

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