title: CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases.
abstract: The chemokines CCL3 and CCL5, as well as their shared receptor CCR1, are believed to play a role in the pathogenesis of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and transplant rejection. In this study we describe the pharmacological properties of a novel small molecular weight CCR1 antagonist, CP-481,715 (quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluorobenzyl)-2(S),7-dihydroxy-7-methyloctyl]amide). Radiolabeled binding studies indicate that CP-481,715 binds to human CCR1 with a Kd of 9.2 nm and displaces 125I-labeled CCL3 from CCR1-transfected cells with an IC50 of 74 nm. CP-481,715 lacks intrinsic agonist activity but fully blocks the ability of CCL3 and CCL5 to stimulate receptor signaling (guanosine 5'-O-(thiotriphosphate) incorporation; IC50 = 210 nm), calcium mobilization (IC50 = 71 nm), monocyte chemotaxis (IC50 = 55 nm), and matrix metalloproteinase 9 release (IC50 = 54 nm). CP-481,715 retains activity in human whole blood, inhibiting CCL3-induced CD11b up-regulation and actin polymerization (IC50 = 165 and 57 nm, respectively) on monocytes. Furthermore, it behaves as a competitive and reversible antagonist. CP-481,715 is >100-fold selective for CCR1 as compared with a panel of G-protein-coupled receptors including related chemokine receptors. Evidence for its potential use in human disease is suggested by its ability to inhibit 90% of the monocyte chemotactic activity present in 11/15 rheumatoid arthritis synovial fluid samples. These data illustrate that CP-481,715 is a potent and selective antagonist for CCR1 with therapeutic potential for rheumatoid arthritis and other inflammatory diseases.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340, USA. Ronald_P_Glaude@Groton.Pfizer.com
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Gladue
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Tylaska
authors.forename: William H
authors.initials: WH
authors.lastname: Brissette
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lira
authors.forename: John C
authors.initials: JC
authors.lastname: Kath
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Poss
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Paradis
authors.forename: Maryrose J
authors.initials: MJ
authors.lastname: Conklyn
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Ogborne
authors.forename: Molly A
authors.initials: MA
authors.lastname: McGlynn
authors.forename: Brett M
authors.initials: BM
authors.lastname: Lillie
authors.forename: Amy P
authors.initials: AP
authors.lastname: DiRico
authors.forename: Erin N
authors.initials: EN
authors.lastname: Mairs
authors.forename: Eric B
authors.initials: EB
authors.lastname: McElroy
authors.forename: William H
authors.initials: WH
authors.lastname: Martin
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Stock
authors.forename: Richard M
authors.initials: RM
authors.lastname: Shepard
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Showell
authors.forename: Kuldeep
authors.initials: K
authors.lastname: Neote
mesh_terms: D000199:Actins / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D039481:CD11b Antigen / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008956:Models, Chemical; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000199:Actins; C515300:CCR1 protein, human; D039481:CD11b Antigen; D018925:Chemokines; D008024:Ligands; D011810:Quinoxalines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C479133:quinoxaline-2-carboxylic acid (4-carbamoyl-1-(3-fluorobenzyl)-2,7-dihydroxy-7-methyloctyl)amide; D020780:Matrix Metalloproteinase 9; D002118:Calcium