MK 0893

Glucagon receptor/IGF-1R antagonist CAS# 870823-12-4

MK 0893

Catalog No. BCC1752----Order now to get a substantial discount!

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Chemical structure

MK 0893

3D structure

Chemical Properties of MK 0893

Cas No. 870823-12-4 SDF Download SDF
PubChem ID 11570626 Appearance Powder
Formula C32H27Cl2N3O4 M.Wt 588.5
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 33.33 mg/mL (56.64 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid
SMILES CC(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
Standard InChIKey DNTVJEMGHBIUMW-IBGZPJMESA-N
Standard InChI InChI=1S/C32H27Cl2N3O4/c1-19(20-3-5-21(6-4-20)32(40)35-12-11-31(38)39)37-30(18-29(36-37)25-14-26(33)17-27(34)15-25)24-8-7-23-16-28(41-2)10-9-22(23)13-24/h3-10,13-19H,11-12H2,1-2H3,(H,35,40)(H,38,39)/t19-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of MK 0893

DescriptionMK 0893 is an inhibitor of both glucagon receptor and IGF-1R with IC50 values of 6.6 nM and 6 nM, respectively.
Targetsglucagon receptorIGF-1R    
IC506.6 nM6 nM    

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.

Reacting condition

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.

Application

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.

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.

MK 0893 Dilution Calculator

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MK 0893 Molarity Calculator

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Preparing Stock Solutions of MK 0893

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.6992 mL 8.4962 mL 16.9924 mL 33.9847 mL 42.4809 mL
5 mM 0.3398 mL 1.6992 mL 3.3985 mL 6.7969 mL 8.4962 mL
10 mM 0.1699 mL 0.8496 mL 1.6992 mL 3.3985 mL 4.2481 mL
50 mM 0.034 mL 0.1699 mL 0.3398 mL 0.6797 mL 0.8496 mL
100 mM 0.017 mL 0.085 mL 0.1699 mL 0.3398 mL 0.4248 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on MK 0893

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.

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References on MK 0893

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)carbo nyl]-beta-alanine (MK-0893) for the treatment of type II diabetes.[Pubmed:22708876]

J Med Chem. 2012 Jul 12;55(13):6137-48.

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-y l]ethyl}phenyl)carbonyl]-beta-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

Description

MK 0893 is a potent and selective glucagon receptor antagonist with an IC50 of 6.6 nM.

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