MK-0812 is a Selective CCR2 Antagonist

Inhibition of monocyte and macrophage function by targeting chemokine receptors represents an attractive strategy for therapeutic intervention in inflammatory diseases. 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). In particular, MK-0812 completely blocks all MCP-1 mediated response in a concentration dependent manner with an IC50 of 3.2 nM.

MK-0812 selectively reduces the peripheral blood monocyte frequency and causes an elevation in the CCR2 ligand CCL2. The addition of MK-0812 to rhesus blood in vitro also inhibits MCP-1 induced monocyte shape change. The IC50 for MK-0812 in vitro whole blood assays is 8 nM. Treatment of the monkeys with MK-0812 by continuous infusion achieves plasma levels of 0.9 nM to 258 nM. In addition, MK-0812 leads to a reduction in the number of monocytes and macrophages. The reduction in the CD68 area in the punch biopsies demonstrates the result.

In this study, researchers also evaluated the ability of MK-0812 to block monocyte migration in vivo. MK0812 (30 mg/kg, p.o.) causes a dose-dependent reduction in circulating Ly6Chi monocytes and a corresponding elevation in the CCR2 ligand CCL2. Moreover, MK-0812 is a suitable pharmacological tool for in vivo studies in mice. MK-0812 (continuous i.v. infusion) maintains a constant level of the drug in the blood.

All in all, CXCR2 acts as a target for rheumatoid arthritis and reveals molecular interactions. Especially, MK-0812 is a selective CCR2 antagonist for the research of inflammatory and homeostatic conditions.

J Immunol Methods. 2010 Jan 31;352(1-2):101-10. Assessment of chemokine receptor function on monocytes in whole blood: In vitro and ex vivo evaluations of a CCR2 antagonist.