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]: |
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Binding assays
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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.
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| Cell experiment [1]: |
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Cell lines
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CHO cells expressing the hGCGR.
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Preparation method
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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.
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Reaction Conditions
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56-1000 nM; 30 min.
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Applications
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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.
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| Animal experiment [1]: |
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Animal models
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hGCGR ob/ob mice.
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Dosage form
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3, 10, and 30 mpk;1 h; administrated orally.
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Applications
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MK 0893 reduces glucose elevation stimulated by glucagon (15 μg/kg) by 30%, 56%, and 81% at 3, 10, and 30 mpk, respectively.
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Other notes
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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.
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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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