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: Ronald P Gladue, Laurie A Tylaska, William H Brissette, Paul D Lira, John C Kath, Christopher S Poss, Matthew F Brown, Timothy J Paradis, Maryrose J Conklyn, Kevin T Ogborne, Molly A McGlynn, Brett M Lillie, Amy P DiRico, Erin N Mairs, Eric B McElroy, William H Martin, Ingrid A Stock, Richard M Shepard, Henry J Showell, Kuldeep Neote
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 42 Pg. 40473-80 (Oct 17 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12909630 (Publication Type: Journal Article)

Chemical References

• Actins
• CCR1 protein, human
• CD11b Antigen
• Chemokines
• Ligands
• Quinoxalines
• Receptors, CCR1
• Receptors, Chemokine
• quinoxaline-2-carboxylic acid (4-carbamoyl-1-(3-fluorobenzyl)-2,7-dihydroxy-7-methyloctyl)amide
• Matrix Metalloproteinase 9
• Calcium

Topics

• Actins (metabolism)
• Arthritis, Rheumatoid (metabolism)
• CD11b Antigen (biosynthesis)
• Calcium (metabolism)
• Cell Line
• Chemokines (metabolism)
• Chemotaxis
• Dose-Response Relationship, Drug
• Humans
• Inflammation
• Inhibitory Concentration 50
• Kinetics
• Ligands
• Matrix Metalloproteinase 9 (metabolism)
• Models, Chemical
• Monocytes (metabolism)
• Protein Binding
• Quinoxalines (chemistry, pharmacology)
• Receptors, CCR1
• Receptors, Chemokine (antagonists & inhibitors, metabolism)
• Signal Transduction
• Transfection
• Up-Regulation