| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
MK-0812 (MK0812) is a novel, potent and selective small molecule CCR2 antagonist with potential anti-Inflammatory and immunomodulatory activity. MK0812 caused an increase in the CCR2 ligand CCL2 and a selective decrease in the frequency of peripheral blood monocytes. The therapeutic potential for targeting CXCR2/CXCR1 in human arthritides is highlighted by the significantly greater impact of CXCR2/CXCR1 antagonism in this model of arthritis compared to CCR2 antagonism. In the tissue and synovial fluid of rheumatoid arthritis patients, neutrophils and monocytes are highly prevalent. It was investigated how small molecule chemokine receptor antagonists, like MK-0812, might prevent these cells from migrating in arthritis caused by anti-collagen antibodies.
| Targets |
CCR2
MK-0812 completely inhibits every MCP-1 mediated response in a concentration-dependent manner, with an IC50 of 3.2 nM. This value is comparable to the potency (IC50 4.5 nM) reported for MK-0812's inhibition of 125I-MCP-1 binding on isolated monocytes. Specifically, the antagonist causes a monocyte forward scatter measurement below unstimulated or basal levels in addition to totally blocking the shape change response to exogenous MCP-1. MK-0812 added to rhesus blood also prevents the shape change of monocytes induced by MCP-1. MK0812 is a powerful and specific small molecule antagonist of CCR2[2]. |
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| ln Vitro |
MK-0812 completely inhibits every MCP-1 mediated response in a concentration-dependent manner, with an IC50 of 3.2 nM. This value is comparable to the potency (IC50 4.5 nM) reported for MK-0812's inhibition of 125I-MCP-1 binding on isolated monocytes. Specifically, the antagonist causes a monocyte forward scatter measurement below unstimulated or basal levels in addition to totally blocking the shape change response to exogenous MCP-1. MK-0812 added to rhesus blood also prevents the shape change of monocytes induced by MCP-1. MK0812 is a powerful and specific small molecule antagonist of CCR2[2].
In human whole blood, MK-0812 completely blocked MCP-1 mediated monocyte shape change in a concentration-dependent manner with an IC50 of 3.2 nM. In rhesus whole blood, MK-0812 inhibited MCP-1 induced monocyte shape change with an IC50 of 8 nM in vitro. The compound also inhibited basal monocyte forward scatter below unstimulated levels in the absence of exogenous agonist, suggesting blockade of endogenous CCR2 signaling. [1] |
| ln Vivo |
MK0812 is administered intravenously continuously in order to keep the drug's blood level steady[1]. The peripheral blood's Ly6G-Ly6Chi monocyte frequency is decreased upon administration of MK0812 at a dose of 30 mg/kg, p.o.; however, the frequency of circulating Ly6G+Ly6C+ neutrophils is unaffected. Furthermore, administration of MK0812 results in a dose-dependent decrease in Ly6Chi monocytes in circulation and an increase in the CCR2 ligand CCL2[2].
In rhesus monkeys, MK-0812 administered by continuous intravenous infusion inhibited monocyte recruitment to the skin in a delayed-type hypersensitivity model induced by tetanus toxoid. The inhibition of monocyte recruitment correlated with ex vivo inhibition of MCP-1 induced monocyte shape change in whole blood from the same animals. [1] |
| Enzyme Assay |
Human whole blood is drawn into EDTA tubes and used right away—within an hour. Blood (200 µL) is pre-incubated for 30 minutes at room temperature with MK-0812 (0.1% final DMSO concentration) for antagonist treated samples. Next, 4 µL of chemokine or buffer and 20 µL of FITC conjugated anti-CD14 antibody are added to each sample and gently mixed. A 100 µL aliquot of the blood mixture is incubated for 10 minutes at 37°C. It is then promptly put on ice and gently fixed for 1 minute with 250 µL of an ice cold fixative (49 mL PBS, 1.0 mL 4% para-formaldehyde). In order to lyse red blood cells, 1.0 mL of an ice-cold lysis solution containing 0.15 M NH4Cl2, 10 mM sodium bicarbonate, and 1 mM EDTA is added. The mixture is then incubated on ice for 20 minutes. Following the complete lysis of red blood cells, 100 µL of 4% para-formaldehyde is added, and flow cytometry is used to analyze the samples for measurements of forward scatter[1].
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| Cell Assay |
The whole blood monocyte shape change assay was performed by incubating EDTA-collected blood with MK-0812 or vehicle, followed by stimulation with MCP-1. After incubation at 37°C, samples were fixed, red blood cells were lysed, and forward scatter of CD14+ monocytes was measured by flow cytometry.
Confocal microscopy confirmed that the change in forward scatter corresponded to a change in monocyte shape from rounded to elongated. [1] |
| Animal Protocol |
Mice: The mice used are 8–10 week old female BALB/c mice. 30 mg/kg oral gavage (p.o.) of SCH563705 or MK0812 in a 0.4% MC solution is used to administer the medication. Using flow cytometry, the frequency of CD11b+Ly6G-Ly6Chi neutrophils and CD11b+Ly6G+Ly6Chi monocytes is ascertained two hours later.
Rhesus monkeys were administered MK-0812 via continuous intravenous infusion using a portable infusion pump to maintain constant plasma levels. Dosing consisted of an initial loading dose (0.0012 to 0.33 mg/kg) followed by continuous infusion (0.0004 to 0.1 mg/h/kg) to achieve target plasma concentrations ranging from ~0.9 to 258 nM. Monocyte recruitment was assessed 24 hours after intradermal challenge with tetanus toxoid, and skin biopsies were collected for immunohistochemical analysis of CD68+ monocytes/macrophages. [1] |
| ADME/Pharmacokinetics |
Plasma drug concentrations were measured 24 hours after continuous intravenous infusion of MK-0812 in rhesus monkeys, ranging from approximately 0.9 to 258 nM, depending on the infusion rate. Inhibition of monocyte morphological changes in vitro was correlated with plasma drug concentration, with an IC50 value of 5 nM. [1]
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| References |
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| Additional Infomation |
MK0812 has been used in clinical trials for the treatment of relapsing-remitting multiple sclerosis. MK-0812 is a small molecule CCR2 antagonist used to inhibit monocyte recruitment in an inflammatory model. Whole blood monocyte morphology changes have been proposed as a potential pharmacodynamic biomarker for evaluating the efficacy of CCR2 antagonists in clinical trials. This assay has shown low donor variability (<20%) and good reproducibility, supporting its application in translational research. [1]
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| Molecular Formula |
C24H34N3O3F3
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|---|---|
| Molecular Weight |
469.54026
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| Exact Mass |
469.255
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| Elemental Analysis |
C, 61.39; H, 7.30; F, 12.14; N, 8.95; O, 10.22
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| CAS # |
624733-88-6
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| Related CAS # |
MK-0812 Succinate; 851916-42-2
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| PubChem CID |
11180808
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
562.0±50.0 °C at 760 mmHg
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| Flash Point |
293.7±30.1 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.538
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| LogP |
2.37
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
692
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| Defined Atom Stereocenter Count |
4
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| SMILES |
O=C([C@]1(C(C)C)C[C@H](N[C@H]2CCOC[C@H]2OC)CC1)N3CCC(N=CC(C(F)(F)F)=C4)=C4C3
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| InChi Key |
MTMDXAIUENDNDL-RJSMDTJLSA-N
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| InChi Code |
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
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| 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
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| Synonyms |
MK0812; MK 0812; MK-0812
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~213 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1297 mL | 10.6487 mL | 21.2974 mL | |
| 5 mM | 0.4259 mL | 2.1297 mL | 4.2595 mL | |
| 10 mM | 0.2130 mL | 1.0649 mL | 2.1297 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00542022 | Completed | Drug: MK0812 / Duration of Treatment: 12 Weeks Drug: Comparator: placebo (unspecified) / Duration of Treatment: 12 Weeks |
Arthritis, Rheumatoid | Merck Sharp & Dohme LLC | June 2004 | Phase 2 |
| NCT00239655 | Terminated | Drug: MK0812 | Relapsing-Remitting Multiple Sclerosis |
Merck Sharp & Dohme LLC | August 2004 | Phase 2 |
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