Received for publication May 6, 2008.
Revised June 28, 2008.
Accepted for publication July 2, 2008.

Pharmacological profile of JNJ-27141491, a non-competitive and orally active antagonist of the human chemokine receptor CCR2

Abstract

The interaction between CC chemokine receptor 2 (CCR2) with monocyte chemoattractant proteins, such as MCP-1, regulates the activation and recruitment of inflammatory leukocytes. In this study, we characterized JNJ-27141491, a thioimidazole derivative, as a non-competitive and orally active functional antagonist of human (h)CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced [³⁵S]GTPS binding, MCP-1, -3 and -4-induced Ca²⁺ mobilization and leukocyte chemotaxis towards MCP-1 (IC₅₀ = 7-97 nM), while it had little or no effect on the function of other chemokine receptors tested. The inhibition of CCR2 function was both insurmountable and reversible, consistent with a non-competitive mode of action. JNJ-27141491 blocked the binding of [¹²⁵I]MCP-1 to human monocytes (IC₅₀ = 0.4 µM), but failed to affect MCP-1 binding to mouse, rat and dog cells (IC₅₀>10 µM). Therefore, transgenic mice, in which the mouse (m)CCR2 gene was replaced by the human counterpart, were generated for in vivo testing. In these mice, oral administration of JNJ-27141491 dose-dependently (5-40 mg/kg, q.d. or b.i.d.) inhibited monocyte and neutrophil recruitment to the alveolar space 48h after intratracheal mMCP-1/LPS instillation. Furthermore, treatment with JNJ-27141491 (20 mg/kg, q.d.) significantly delayed the onset and temporarily reduced neurological signs in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Taken together, these results identify JNJ-27141491 as a non-competitive, functional antagonist of hCCR2, capable of exerting oral anti-inflammatory activity in transgenic hCCR2-expressing mice.

Key words: CCR2, CCR2 antagonist, EAE, MCP-1, chemokine receptor antagonism, monocyte