title: 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 5'-O-(3-[(35)S]thio)triphosphate binding; MCP-1, -3, and -4-induced Ca(2+) mobilization; and leukocyte chemotaxis toward MCP-1 (IC(50) = 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 (125)I-MCP-1 to human monocytes (IC(50) = 0.4 microM), but it failed to affect MCP-1 binding to mouse, rat, and dog cells (IC(50) > 10 microM). 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. (once daily) or b.i.d.] inhibited monocyte and neutrophil recruitment to the alveolar space 48 h after intratracheal mMCP-1/lipopolysaccharide 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 model of multiple sclerosis. Taken together, these results identify JNJ-27141491 as a noncompetitive, functional antagonist of hCCR2, capable of exerting oral anti-inflammatory activity in transgenic hCCR2-expressing mice.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. mieke.buntinx@telenet.be
authors.forename: Mieke
authors.initials: M
authors.lastname: Buntinx
authors.forename: Bart
authors.initials: B
authors.lastname: Hermans
authors.forename: Jan
authors.initials: J
authors.lastname: Goossens
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.forename: Ron A H J
authors.initials: RA
authors.lastname: Gilissen
authors.forename: Julien
authors.initials: J
authors.lastname: Doyon
authors.forename: Staf
authors.initials: S
authors.lastname: Boeckx
authors.forename: Erwin
authors.initials: E
authors.lastname: Coesemans
authors.forename: Guy
authors.initials: G
authors.lastname: Van Lommen
authors.forename: Jean P
authors.initials: JP
authors.lastname: Van Wauwe
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051381:Rats; D011917:Rats, Inbred Lew; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D007093:Imidazoles; C532123:JNJ-27141491; D054390:Receptors, CCR2; D002118:Calcium