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Purity: ≥98%
MK0812 Succinate (MK-0812) is a novel, potent and selective small molecule CCR2 antagonist with 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 is a potent and selective antagonist of CCR2 [1]. MK-0812 exhibits concentration-dependent partial inhibition of all MCP-1-mediated responses, with an IC50 of 3.2 nM. This amount is comparable to the potency found in MK-0812's suppression of 125I-MCP-1 binding on isolated monocytes (IC50 4.5 nM). MK-0812, in fact, not only completely prevents the exogenous MCP-1-induced shape change response, but it also causes a monocyte forward scatter measurement that is lower than basal or unstimulated levels. MK-0812 also prevents MCP-1-induced monocyte morphological change when added to rhesus blood. In whole blood assays, the IC50 for MK-0812 is 8 nM[2]. |
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| ln Vitro |
MK-0812 is a potent and selective antagonist of CCR2 [1]. MK-0812 exhibits concentration-dependent partial inhibition of all MCP-1-mediated responses, with an IC50 of 3.2 nM. This amount is comparable to the potency found in MK-0812's suppression of 125I-MCP-1 binding on isolated monocytes (IC50 4.5 nM). MK-0812, in fact, not only completely prevents the exogenous MCP-1-induced shape change response, but it also causes a monocyte forward scatter measurement that is lower than basal or unstimulated levels. MK-0812 also prevents MCP-1-induced monocyte morphological change when added to rhesus blood. In whole blood assays, the IC50 for MK-0812 is 8 nM[2].
MK-0812 completely blocked MCP-1-mediated monocyte shape change in human whole blood 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. Treatment with CCR2 antagonists (including MK-0812) reduced basal monocyte forward scatter below unstimulated levels in whole blood, suggesting inhibition of endogenous chemokine signaling.[2] |
| ln Vivo |
MK-0812 (30 mg/kg, p.o.) decreases the frequency of Ly6G-Ly6Chi monocytes in peripheral blood, but has no effect on the frequency of Ly6G+Ly6C+ neutrophils in circulation. Additionally, administration of MK-0812 results in an increase in the CCR2 ligand CCL2 and a dose-dependent decrease in circulating Ly6Chi monocytes[1]. To keep the amount of MK-0812 in the blood at a steady level, it is continuously infused intravenously[2].
In a mouse model of anti-collagen antibody-induced arthritis (ABIA), oral administration of MK0812 (30 mg/kg, twice daily) had no discernable effect on clinical disease scores or paw swelling, both in the standard LPS-boosted model and in a TNFα-driven variant of the model. Despite the lack of efficacy on arthritis, MK0812 demonstrated clear pharmacodynamic activity in naïve mice: it selectively reduced the frequency of Ly6C^(high) monocytes in the peripheral blood in a dose-dependent manner. Concomitantly, treatment with MK0812 caused a dose-dependent elevation in plasma levels of the CCR2 ligand CCL2, confirming target engagement and blockade of the CCR2-CCL2 axis. This effect was specific, as MK0812 had no impact on circulating neutrophil frequency or plasma levels of the CXCR2 ligand CXCL1. [1] |
| Cell Assay |
Whole blood monocyte shape change assay: Human or rhesus blood was collected in EDTA tubes and used within 1 hour. Blood was pre-incubated with antagonist or vehicle for 20–30 minutes at room temperature, then stimulated with chemokine (e.g., MCP-1) for 7–10 minutes at 37°C. Samples were fixed, red blood cells were lysed, and monocytes were stained with anti-CD14 antibody. Forward scatter of CD14-positive monocytes was measured by flow cytometry to assess shape change.
For ex vivo assays in rhesus monkeys, blood was collected before and after drug administration, and MCP-1-induced shape change was measured similarly. Monocyte chemokine receptor expression was assessed by staining whole blood with anti-CCR1, anti-CCR2, or anti-CCR5 antibodies and analyzing by flow cytometry.[2] |
| Animal Protocol |
Mice: The mice used are 8–10 week old female BALB/c mice. SCH563705 or MK-0812 are given orally at a dose of 30 mg/kg using a 0.4% methylcellulose (MC) solution (p.o.). Using flow cytometry, the frequency of CD11b+Ly6G+Ly6C+ neutrophils and CD11b+Ly6G+Ly6Chi monocytes is ascertained two hours later[1].
Pharmacodynamic Study in Naïve Mice: MK0812 was dissolved in a vehicle of 0.4% hydroxypropyl methylcellulose (MC) and administered to naïve BALB/c mice by oral gavage (p.o.) at various doses (e.g., 3, 10, 30 mg/kg). Blood was collected 2 hours post-dose for flow cytometric analysis of immune cell populations and ELISA measurement of plasma chemokines. Efficacy Study in Arthritis Models: In the ABIA model, arthritis was induced in BALB/c mice via intraperitoneal injection of an anti-collagen antibody cocktail on day 0, followed by an LPS boost (i.p.) or local TNFα injection (s.c. into footpads) on day 3. MK0812 (30 mg/kg) or vehicle (0.4% MC) was administered orally, twice daily (b.i.d.), from day 0 to day 7. Clinical scores and paw thickness were monitored daily. [1] |
| ADME/Pharmacokinetics |
In the ABIA efficacy study, the mean plasma concentration (representing trough concentration) of MK0812, measured 12 hours after the last dose, was 327 nM. This concentration was reported to be 17 times the IC₅₀ value for the compound against the CCR2 receptor, indicating good target coverage throughout the dosing interval.
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| References |
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| Additional Infomation |
MK0812 is a selective small molecule CCR2 receptor antagonist, which mediates monocyte migration. As described in the paper, its development for the treatment of rheumatoid arthritis (RA) has been terminated due to a lack of clinical efficacy in human trials. This study observed that despite achieving high receptor occupancy in a mouse ABIA model, efficacy remained insufficient, suggesting that blocking CCR2 alone may not be enough to improve arthritis symptoms in this model. Potential reasons include functional redundancy of other chemokine receptors on monocytes, such as CCR1. This study confirms that MK0812 is an effective pharmacological tool for studying CCR2 function in vivo, as evidenced by its specific effects on monocyte frequency and CCR2 levels. [1]
|
| Molecular Formula |
C28H40F3N3O7
|
|---|---|
| Molecular Weight |
587.628318786621
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| Exact Mass |
587.28
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| Elemental Analysis |
C, 57.23; H, 6.86; F, 9.70; N, 7.15; O, 19.06
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| CAS # |
851916-42-2
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| Related CAS # |
MK-0812; 624733-88-6
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| PubChem CID |
60196412
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
41
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| Complexity |
793
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CC(C)[C@@]1(CC[C@H](C1)[NH2+][C@H]2CCOC[C@H]2OC)C(=O)N3CCC4=C(C3)C=C(C=N4)C(F)(F)F.C(CC(=O)[O-])C(=O)O
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| InChi Key |
WPPJJJUIDYHHSM-PXUYIWLPSA-N
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| InChi Code |
InChI=1S/C24H34F3N3O3.C4H6O4/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;5-3(6)1-2-4(7)8/h10,12,15,18,20-21,29H,4-9,11,13-14H2,1-3H3;1-2H2,(H,5,6)(H,7,8)/t18-,20+,21-,23+;/m1./s1
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| Chemical Name |
butanedioic acid;[(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 |
MK-0812 Succinate; MK0812 Succinate; MK-0812; MK 0812 Succinate
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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: ≥ 32 mg/mL (~54.5 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.25 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 (4.25 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.25 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7018 mL | 8.5088 mL | 17.0175 mL | |
| 5 mM | 0.3404 mL | 1.7018 mL | 3.4035 mL | |
| 10 mM | 0.1702 mL | 0.8509 mL | 1.7018 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.
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