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MK-0812

Names

[ CAS No. ]:
624733-88-6

[ Name ]:
MK-0812

[Synonym ]:
1,5-Anhydro-2,3-dideoxy-3-{[(1R,3S)-3-isopropyl-3-{[3-(trifluormethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol
((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine
CS-0344
MK-0812
N-((1R,3S)-3-isopropyl-3-[[3-trifluoromethyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl]-cyclopentyl)-N-[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]-amine
1,5-Anhydro-2,3-dideoxy-3-{[(1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol
D-erythro-Pentitol, 1,5-anhydro-2,3-dideoxy-3-[[(1R,3S)-3-[[7,8-dihydro-3-(trifluoromethyl)-1,6-naphthyridin-6(5H)-yl]carbonyl]-3-(1-methylethyl)cyclopentyl]amino]-4-O-methyl-

Biological Activity

[Description]:

MK-0812 is a potent and selective CCR2 antagonist with low nM affinity for CCR2 on human monocytes.

[Related Catalog]:

Research Areas >> Inflammation/Immunology

[Target]

CCR2


[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].

[Kinase Assay]

Human whole blood is collected in EDTA tubes and used within 1 h of blood collection. For antagonist treated samples, blood (200 µL) is pre-incubated with MK-0812 (0.1% final DMSO concentration) for 30 min at room temperature. After which, 20 µL of FITC conjugated anti-CD14 antibody and 4 µL of chemokine or buffer is added to each sample and mixed lightly. An aliquot (100 µL) of the blood mixture is incubated for 10 min at 37°C, immediately placed on ice and lightly fixed with 250 µL of ice cold fixative (49 mL PBS, 1.0 mL 4% para-formaldehyde) for 1 min. Red blood cells are lysed by adding 1.0 mL of ice cold lysis solution (0.15 M NH4Cl2, 10 mM sodium bicarbonate, and 1 mM EDTA), and incubated for 20 min on ice. After complete lysis of red blood cells, 100 µL of 4% para-formaldehyde is added and the samples are analyzed by flow cytometry for forward scatter measurements[1].

[Animal admin]

Mice[2] Female BALB/c mice are used between 8 and 10 weeks of age. SCH563705 or MK0812 are administered in a 0.4% MC solution by 30 mg/kg oral gavage (p.o.). Two hours later, the frequency of CD11b+Ly6G-Ly6Chi monocytes and CD11b+Ly6G+Ly6C+ neutrophils is determined by flow cytometry.

[References]

[1]. Wisniewski T, 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 Jan 31;352(1-2):101-10.

[2]. Min SH, et al. Pharmacological targeting reveals distinct roles for CXCR2/CXCR1 and CCR2 in a mouse model of arthritis.Biochem Biophys Res Commun. 2010 Jan 1;391(1):1080-6.


[Related Small Molecules]

INCB3344 | Cenicriviroc | INCB8761(PF-4136309) | RS504393 | RS-102895 hydrochloride | BX 471 | TAK-779 | Vercirnon | MK-0812 Succinate | AZD 2098 | CCX140 | INCB 3284 | ZK 756326 | CCR2-RA-[R] | BMS-813160

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Boiling Point ]:
562.0±50.0 °C at 760 mmHg

[ Molecular Formula ]:
C24H34F3N3O3

[ Molecular Weight ]:
469.540

[ Flash Point ]:
293.7±30.1 °C

[ Exact Mass ]:
469.255219

[ PSA ]:
63.69000

[ LogP ]:
2.37

[ Vapour Pressure ]:
0.0±1.5 mmHg at 25°C

[ Index of Refraction ]:
1.538

[ Storage condition ]:
2-8℃

Precursor & DownStream

Precursor

DownStream

Related Compounds