Pharmacological Profile of JNJ-27141491 [(S)-3-[3,4-Difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl Acid Methyl Ester], as a Noncompetitive 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 (S)-3-[3,4-difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester (JNJ-27141491) as a noncompetitive and orally active functional antagonist of human (h)CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding; MCP-1, -3, and -4-induced Ca 2ϩ mobilization; and leukocyte chemotaxis toward MCP-1 (IC 50 ϭ 7-97 nM), whereas 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 noncompetitive mode of action. JNJ-27141491 blocked the binding of CCR2 is a G protein-coupled chemokine receptor, expressed on monocytes, macrophages, basophils, dendritic cells, natural killer cells, and activated T lymphocytes, that mediates the activation and movement of responsive leukocytes along a chemotactic gradient. CCR2 has two isoforms (CCR2A and CCR2B) that are generated by alternative splicing and differ only in their carboxyl-terminal tail. Leukocytes predominantly express the longer CCR2B variant (Tanaka et al., 2002). CCR2B (henceforth called CCR2) is activated by several members of the CC-chemokine subfamily, consisting of monocyte chemoattractant protein-1 (MCP-1/CCL2), MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13, and MCP-5/CCL16. MCP-1 exclusively interacts with CCR2 and is therefore recognized as the prime CCR2 agonist. Engagement of CCR2 inhibits adenylyl cyclase, promotes intracellular calcium mobilization, stimulates mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, and promotes che-

Multiple Binding Sites for Small-Molecule Antagonists at the CC Chemokine Receptor 2

“…All antagonists displaced 125 I-CCL2 from the receptor ( Fig. 3A; Table 2) with affinities similar to previously reported data (Mirzadegan et al, 2000;Brodmerkel et al, 2005;Zou et al, 2007;Buntinx et al, 2008;Cherney et al, 2008;Moree et al, 2008). BMS22, RS504393, and Teijin were also able to displace (Table 2).…”

A New Monocyte Chemotactic Protein-1/Chemokine CC Motif Ligand-2 Competitor Limiting Neointima Formation and Myocardial Ischemia/Reperfusion Injury in Mice

“…Initially, promising biopharmaceutical approaches like the anti-CCL2 monoclonal antibody ABN912 (37) or the P8A CCL2 mutant (11) showed no or insufficient efficacy to reach final stages of drug development. On the other hand, small molecule CCR2 inhibitors remain in active but still early development and, like the JNJ-27141491 compound (38), may have significant advantages over biopharmaceuticals due to oral bioavailability. In general, strategies that encompass the direct blockade of chemokine receptors by small molecule antagonists have returned rather disappointing results (39).…”

Biomarkers of neurological status in HIV infection: A 3‐year study

“…MCP‐1 may influence viral replication within the brain 45, which occurs primarily in cells of monocytic lineage (monocyte‐derived macrophages and microglia), alter the inflammatory cascade 46 or otherwise interact with viral proteins 38, 47–52. Experimental evidence suggests that MCP‐1 primes the responsiveness of glia to inflammatory stimuli 53 and an MCP‐1 antagonist delays onset and reduces neurological signs associated with neuroinflammation 54. Both MCP‐1 levels (plasma and CSF) and symptomatic neurological progression have been identified as predictors of death in HIV infection ( e.g.…”