CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases.
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.
Gladue
Ronald P
RP
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. Ronald_P_Glaude@Groton.Pfizer.com
Tylaska
Laurie A
LA
Brissette
William H
WH
Lira
Paul D
PD
Kath
John C
JC
Poss
Christopher S
CS
Brown
Matthew F
MF
Paradis
Timothy J
TJ
Conklyn
Maryrose J
MJ
Ogborne
Kevin T
KT
McGlynn
Molly A
MA
Lillie
Brett M
BM
DiRico
Amy P
AP
Mairs
Erin N
EN
McElroy
Eric B
EB
Martin
William H
WH
Stock
Ingrid A
IA
Shepard
Richard M
RM
Showell
Henry J
HJ
Neote
Kuldeep
K
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
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