MK-0812

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Background

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].

[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.