MK-0812antagonist of chemokine receptor CCR-2 CAS# 624733-88-6 |
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Quality Control & MSDS
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| Cas No. | 624733-88-6 | SDF | Download SDF |
| PubChem ID | 11180808 | Appearance | Powder |
| Formula | C24H34F3N3O3 | M.Wt | 469.55 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO | ||
| Chemical Name | [(1S,3R)-3-[[(3S,4S)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[3-(trifluoromethyl)-7,8-dihydro-5H-1,6-naphthyridin-6-yl]methanone | ||
| SMILES | CC(C)C1(CCC(C1)NC2CCOCC2OC)C(=O)N3CCC4=NC=C(C=C4C3)C(F)(F)F | ||
| Standard InChIKey | MTMDXAIUENDNDL-RJSMDTJLSA-N | ||
| Standard InChI | InChI=1S/C24H34F3N3O3/c1-15(2)23(7-4-18(11-23)29-20-6-9-33-14-21(20)32-3)22(31)30-8-5-19-16(13-30)10-17(12-28-19)24(25,26)27/h10,12,15,18,20-21,29H,4-9,11,13-14H2,1-3H3/t18-,20+,21-,23+/m1/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. |
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| 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. |
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| 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. | ||
| Description | MK-0812 is a potent and selective CCR2 antagonist with low nM affinity for CCR2 on human monocytes.In Vitro:MK-0812 completely blocks all MCP-1 mediated response in a concentration dependent manner, with an IC50 of 3.2 nM. This value is similar to the potency observed for the inhibition of 125I-MCP-1 binding by MK-0812 on isolated monocytes (IC50 4.5 nM). In fact, the antagonist not only completely blocks the shape change response to exogenous MCP-1, but also results in a monocyte forward scatter measurement below unstimulated or basal levels. The addition of MK-0812 to rhesus blood also inhibits MCP-1 induced monocyte shape change. The IC50 for MK-0812 in whole blood assays is 8 nM[1] MK0812 is a potent and selective small molecule CCR2 antagonist[2].In Vivo:MK-0812 is administered by continuous i.v. infusion to maintain a constant level of the drug in blood[1]. Administration of MK0812 at 30 mg/kg, p.o. reduces the frequency of Ly6G-Ly6Chi monocytes in the peripheral blood, while no impact on circulating Ly6G+Ly6C+ neutrophil frequency is observed. In addition, MK0812 treatment causes a dose-dependent reduction in circulating Ly6Chi monocytes and a corresponding elevation in the CCR2 ligand CCL2[2]. References: | |||||
MK-0812 Dilution Calculator
MK-0812 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.1297 mL | 10.6485 mL | 21.297 mL | 42.594 mL | 53.2425 mL |
| 5 mM | 0.4259 mL | 2.1297 mL | 4.2594 mL | 8.5188 mL | 10.6485 mL |
| 10 mM | 0.213 mL | 1.0648 mL | 2.1297 mL | 4.2594 mL | 5.3242 mL |
| 50 mM | 0.0426 mL | 0.213 mL | 0.4259 mL | 0.8519 mL | 1.0648 mL |
| 100 mM | 0.0213 mL | 0.1065 mL | 0.213 mL | 0.4259 mL | 0.5324 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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MK-0812 is an antagonist of chemokine receptor CCR-2 [1].
C-C chemokine receptor type 2 (CCR-2) is a chemokine receptor expressing on monocytes and macrophages and plays a critical and apparently non-redundant role in orchestrating the trafficking of monocytes to tissues [1].
In human whole blood, MK-0812 completely blocked all MCP-1 mediated response with IC50 value of 3.2 nM in a concentration dependent way, which is similar to the inhibition of 125I-MCP-1 binding by MK-0812 on isolated monocytes (IC50 4.5 nM). Also, MK-0812 resulted in a monocyte forward scatter measurement below unstimulated or basal levels. In rhesus whole blood, MK-0812 inhibited monocyte shape change with IC50 value of 8 nM. MK-0812 inhibited monocyte recruitment in a dose-dependent way which related with the inhibition of MCP-1 induced monocyte shape change [1].
In naive BALB/c mice, MK-0812 (30 mg/kg) reduced the frequency of Ly6G-Ly6Chi monocytes in the peripheral blood. In addition, MK-0812 reduced circulating Ly6Chi monocytes and increased the CCR2 ligand CCL2 in a dose-dependent way [2].
References:
[1]. Wisniewski T, Bayne E, Flanagan J, et al. Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist. J Immunol Methods, 2010, 352(1-2): 101-110.
[2]. Min SH, Wang Y, Gonsiorek W, et al. Pharmacological targeting reveals distinct roles for CXCR2/CXCR1 and CCR2 in a mouse model of arthritis. Biochem Biophys Res Commun, 2010, 391(1): 1080-1086.
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Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist.[Pubmed:19913021]
J Immunol Methods. 2010 Jan 31;352(1-2):101-10.
Inhibition of monocyte and macrophage function by targeting chemokine receptors represents an attractive strategy for therapeutic intervention in inflammatory diseases. We describe an assay to assess chemokine receptor function on whole blood monocytes by measuring chemokine stimulated change in cell shape as measured by flow cytometry. The relative potential of the chemokine receptors CCR1, CCR2, CCR5, CX(3)CR1, and CXCR4 to activate monocytes in whole blood was evaluated and compared. Analysis of MCP-1 response for monocytes in blood from numerous donors revealed that the assay method had excellent intra-donor reproducibility and sensitivity. Further, the utility of this assay to determine target engagement by chemokine receptor antagonists was demonstrated using a CCR2 antagonist in rhesus monkeys. Blockade of CCR2 on whole blood monocytes was demonstrated ex vivo on blood samples collected from rhesus monkeys administered a small molecule CCR2 antagonist (MK-0812). Using a delayed-type hypersensitivity reaction to elicit monocyte recruitment to the skin of rhesus monkeys, we also evaluated the ability of MK-0812 to block monocyte migration in vivo. Blockade of CCR2 stimulation of whole blood monocytes was correlated with the inhibition of monocyte recruitment to the skin, validating the potential to use this approach in the evaluation of dose selection for chemokine receptor antagonists clinically.
Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice.[Pubmed:28332276]
Diabetes Obes Metab. 2017 Oct;19(10):1468-1472.
Diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD) are common diabetic complications with limited treatment options. Experimental studies show that targeting inflammation using chemokine receptor (CCR) antagonists ameliorates DKD, presumably by reducing macrophage accumulation or activation. As inflammation is implicated in DPN development, we assessed whether CCR2 and CCR5 antagonism could also benefit DPN. Five-week-old ob/ob mice were fed a diet containing MK-0812, a dual CCR2-CCR5 receptor antagonist, for 8 weeks; DPN, DKD and metabolic phenotyping were then performed to determine the effect of CCR inhibition. Although MK-0812 reduced macrophage accumulation in adipose tissue, the treatment had largely no effect on metabolic parameters, nerve function or kidney disease in ob/ob mice. These results conflict with published data that demonstrate a benefit of CCR antagonists for DKD and hyperglycaemia. We conclude that CCR signaling blockade is ineffective in ob/ob mice and suspect that this is explained by the severe hyperglycaemia found in this model. It remains to be determined whether MK-0812 treatment, alone or in combination with improved glycaemic control, is useful in preventing diabetic complications in alternate animal models.
CC chemokine ligand 2 and CXC chemokine ligand 8 as neutrophil chemoattractant factors in canine idiopathic polyarthritis.[Pubmed:27863550]
Vet Immunol Immunopathol. 2016 Dec;182:52-58.
Canine idiopathic polyarthritis (IPA) is characterized by increased numbers of polymorphonuclear leukocytes (PMNs) in the synovial fluid (SF). In humans, CC chemokine ligand 2 (CCL2) and CXC chemokine ligand 8 (CXCL8) recruit monocytes and neutrophils, respectively, and are involved in various inflammatory disorders. The aim of this study was to assess the roles of these chemokines in driving PMNs infiltration into the joints of dogs with IPA. SF samples were collected from dogs with IPA (n=19) and healthy controls (n=8), and the concentrations of SF CCL2 and CXCL8 were determined by ELISA. Dogs with IPA had significantly higher concentrations of CCL2 (3316+/-2452pg/ml, mean+/-SD) and CXCL8 (3668+/-3879pg/ml) compared with the healthy controls (235+/-45pg/ml and <15.6pg/ml, respectively). Then, an in vitro chemotaxis assay was performed using a modified Boyden chamber (pore size: 3mum). SF from IPA dogs had a chemoattractant activity for PMNs that purified from the peripheral blood of a healthy dog. We subsequently found that combination treatment with MK-0812 (an antagonist of CCL2 receptor) and repertaxin (an antagonist of CXCL8 receptors) significantly inhibited the migration of PMNs to SF from IPA dogs. Thus, expression of the CCL2 receptor (chemokine (CC motif) receptor 2 (CCR2)) was examined using polymerase chain reaction and immunocytochemistry. Canine peripheral blood PMNs exhibited significantly higher CCR2 mRNA expression levels than those in monocytes. In addition, we observed strong CCR2 expression on PMNs obtained from healthy controls and IPA dogs, although mononuclear cells did not express CCR2. Taken together, the data suggest that CCL2 acts as a canine PMNs chemotactic factor as well as CXCL8 and both CCL2 and CXCL8 facilitate the infiltration of PMNs into the joints of dogs with IPA.
