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 K d 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. 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 K d 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. Rheumatoid arthritis is a chronic inflammatory disease affecting 0.5–2% of the population in the Western world, the majority of whom are female. Central to the pathogenesis of this disease is the infiltration of monocytes into synovial tissue. This is supported by the predominance of monocytes in the joint during flare (1Cutolo M. Sulli A. Barone A. Seriolo B. Accardo S. Clin. Exp. Rheum. 1993; 11: 331-339PubMed Google Scholar, 2Tak P.P. Smeets T.J.M. Daha M.R. Kluin P.M Meijers K.A.E. Brand R. 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Consequently, an agent that inhibits monocyte infiltration into synovial tissue has the potential to decrease tissue damage and joint destruction, thus, providing a novel therapy for rheumatoid arthritis. Leukocyte infiltration into inflammatory sites is believed to be regulated by small molecular weight cytokines known as chemokines. Chemokines are 7–10-kDa proteins that can be divided into four groups (CC, CXC, CX3C, and C) depending on the spacing of their N-terminal cysteine residues. Approximately 40 different chemokines have been identified. Some of these are constitutively expressed and play a crucial role in development and lymph node architecture. However, most chemokines are specifically induced at inflammatory sites during disease (6Proudfoot A.E. Nat. Rev. Immunol. 2002; 2: 106-115Crossref PubMed Scopus (613) Google Scholar). Chemokines are of interest as therapeutic targets because they exert their effects through seven-transmembrane G-protein-coupled receptors, well precedented drug targets. Although chemokines are best known for their ability to stimulate cell migration, they also have additional activities that can contribute to tissue damage and inflammation including enhancing T cell activation (7Ward S.G. Bacon K. Westwick J. Immunity. 1998; 9: 1-11Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar), regulating TH-1/TH-2 polarization (8Gao J.-L. Wynn T.A. Chang Y. Lee E.J. Broxmeyer H.E. Cooper S. Tiffany H.L. Westphal H. Kwon-Chung J. Murphy P.M. J. Exp. Med. 1997; 185: 1959-1968Crossref PubMed Scopus (387) Google Scholar, 9Colantonio L. Iellem A. Clissi B. Pardi R. Rogge L. Sinigaglia F. D'Ambrosio D. Blood. 1999; 94: 2981-2989Crossref PubMed Google Scholar, 10Weber C. Weber K.S.C. Klier C. Gu S. Wank R. Horuk R. Nelson P.J. 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In these studies, the levels of CCL3 and monocytes in synovial tissue were directly proportional to the magnitude of joint pain (2Tak P.P. Smeets T.J.M. Daha M.R. Kluin P.M Meijers K.A.E. Brand R. Meinders A.E. Breedveld F.C. Arth. Rheum. 1997; 40: 217-225Crossref PubMed Scopus (473) Google Scholar). The role of these chemokines in the pathogenesis of arthritis is also supported by human genetic association studies (24Makki R.F. al Sharif F. Gonzalez-Gay M.A. Garcia-Porrua C. Ollier W.E. Hajeer A.H. Clin. Exp. Rheumatol. 2000; 18: 391-393PubMed Google Scholar) and by the beneficial effects observed in animal models of arthritis using neutralizing antibodies and receptor antagonists (25Plater-Zyberk C. Hoogewerf A.J. Proudfoot A.E. Power C.A. Wells T.N. Immunol. Lett. 1997; 57: 117-120Crossref PubMed Scopus (208) Google Scholar, 26Barnes D.A. Tse J. Kaufhold M. Owen M. Hesselgesser J. Strieter R. Horuk R. Perez H.D. J. Clin. Invest. 1998; 101: 2910-2919Crossref PubMed Scopus (178) Google Scholar, 27Kasama T. Strieter R.M. Lukacs N.W. Lincoln P.M. Burdick M.D. Kunkel S.L. J. Clin. Invest. 1995; 95: 2868-2876Crossref PubMed Scopus (260) Google Scholar). The potential importance of CCR1 in the pathogenesis of rheumatoid arthritis coupled with the well known success in identifying antagonists of G-protein-coupled receptors prompted us to initiate a search for small molecular weight antagonists of CCR1. These efforts led to the of the novel antagonist, In this study we describe the in vitro properties of CP-481,715 and its ability to inhibit and calcium and matrix Furthermore, CP-481,715 retains activity in whole blood, and as for its potential therapeutic we its ability to inhibit the monocyte chemotactic activity induced by synovial fluid from rheumatoid arthritis These studies that CCR1 a novel therapeutic to monocyte infiltration into inflammatory sites as the synovial tissue. CCR1 antagonist CP-481,715 (quinoxaline-2-carboxylic acid 1) and were by the CCL3 from chemokines were from and for by and were from and were from from Dulbecco's phosphate-buffered calcium and and were from from and were from for cell of and cells were as K. D. Horuk R. Schall T.J. 1993; Full Text PDF PubMed Scopus Google Scholar). and cells were from at the were in for and The human cell in and and CP-481,715 were with CCR1-transfected cells as K. D. Horuk R. Schall T.J. 1993; Full Text PDF PubMed Scopus Google Scholar). The of CCR1 receptors on the cells to be were to by and into at the the of the cells were in and in the at a of were into a and with CCL3 125I-labeled CCL5 activity in the of of CP-481,715 at for The by through a with and with The in well using a the of of binding in studies using CCL3 nm). The K d for 125I-labeled CCL3 to be nm. on CCR1-transfected cells were using of cells were to that were for the nm CCL3 to of the in the of of CP-481,715 and using an the potential for agonist also on in the of CP-481,715 of blood from normal in and to and at were from the and with blood cells were by were to to chemotaxis in chemotaxis from as C.A. T.J. Loetscher M. Gladue R.P. B. K. J. Exp. Med. 1998; PubMed Scopus Google Scholar). were in to the of the with the and of the were to the in the of of and the for in a at the the cells were from the and the of the The of the with and the of cells in were with a for cells a chemotaxis cells were to the and the for In this and the of cells as to the and the chemotaxis at for The and the at for The the and to the The were for at a The of cells by the of the on a at nm. CCR1-transfected cells were and at in The cells were with and with and at mobilization using a the of CP-481,715 and CCL3 9 were in at in tissue nm CCL5 to the cells in the of of were for at and and the of in the by CD11b up-regulation on monocytes in human whole blood as K. 1996; PubMed Scopus (21) Google Scholar). blood were at for in the of of CCL3 to the blood at the were in an to the were by of and The cells were at for at CD11b on monocytes by cell blood in with of CP-481,715 for at CCL3 and the by cell the cells were by with PBS, and for at in the with a and The cells were with and the using a of CP-481,715 and of on CCR1 binding using CCR1-transfected cells used to for small molecular weight that inhibit CCL3 binding to CCR1. of from this led to the of acid as the in binding demonstrated that CP-481,715 displaces 125I-labeled CCL3 from CCR1-transfected cells in a (IC50 = 74 nm). were observed with 125I-labeled CCL5 its binding were also with in binds to human cells with a K d of 9.2 nm. These data that CP-481,715 binds to human CCR1 and its with CP-481,715 with the CCR1 receptor both agonist antagonist we to this from a receptor activation, to the of receptors is to the binding of and the of The release of these a of calcium activation, in the of to the receptor to its The in signaling can be by the of the of in cells a of receptor activity that by that CP-481,715 as an agonist A.J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In CP-481,715 to CCL3 in a (IC50 of 210 nm). CP-481,715 but the effects of CP-481,715 on CCR1 function by calcium mobilization in CCR1-transfected In these studies CP-481,715 directly calcium its of intrinsic agonist activity In as in calcium mobilization induced by CCL3 by CP-481,715 in a The of CP-481,715 to this directly proportional to the of CCL3 a in IC50 with in CCL3 This data that CP-481,715 is a competitive antagonist of CCR1. that CP-481,715 (e.g. by inhibiting we on monocytes that both CCR1 and in calcium mobilization induced by cells using CCL3 CP-481,715 to inhibit but calcium mobilization CP-481,715 directly calcium mobilization on that the effects of CP-481,715 were through with CCR1 and through effects on its we also calcium mobilization on cells because both CCL3 and CCL5 also with this CP-481,715 inhibit calcium mobilization in cells in to these studies indicate that CP-481,715 the CCR1 receptor, lacks intrinsic agonist directly with its and CP-481,715 Leukocyte major of chemokines is their ability to and the infiltration of these cells into sites of to the activity of CP-481,715 on CCR1 in a that be for we a of the effects of CP-481,715 on in CP-481,715 the chemotaxis of cells and human peripheral blood monocytes to an of CCL3 with an IC50 of and 55 nm, CP-481,715 also the chemotaxis of monocytes to other CCR1 including CCL5 and and to inhibit the to the shared with both CCR1 and on monocytes of CP-481,715 to inhibit the chemotaxis of human monocytes in to the that CP-481,715 exert effects on cells that with calcium mobilization studies demonstrated a proportional the of CP-481,715 to inhibit activity and the of we the effects were observed on in the of CP-481,715 to inhibit 90% of the chemotactic to CCL3 directly on the of agonist used to stimulate the the IC50 for CP-481,715 and nm using CCL3 of and nm, were also observed CCL5 used as the agonist These studies that CP-481,715 is a competitive antagonist of CCR1. for a receptor antagonist is a of the antagonist with the receptor in use in to the effects of CP-481,715 were we cells to of CP-481,715 to for the of these cells in to cells their ability to to CCL3 that the effects of CP-481,715 on CCR1 are fully of CP-481,715 for a panel of G-protein-coupled receptors using binding In activity observed at a of Furthermore, drug as as inhibit receptor binding of the to cells expressing and and inhibit the chemotaxis of human cells to the chemokines and These indicate that CP-481,715 is >100-fold selective for CCR1. In to its as compared with other receptors, CP-481,715 is also selective for the human receptor and inhibit the effects of CCL3 on as demonstrated with and whole blood studies at to of G-protein-coupled receptors for activity with CP-481,715 in a of CP-481,715 on CD11b in crucial for therapeutic agents is their ability to activity in the of This be for chemokine receptor antagonists the cells into inflammatory sites in to a chemotactic from the peripheral we two of CCR1 up-regulation and in whole The up-regulation of as the of to the a to cell in CP-481,715 CD11b up-regulation on monocytes in human blood IC50 from different = nm). an of whole blood activity that be of cell migration, we also actin polymerization on monocytes in to CP-481,715 also CCL3-induced actin polymerization in human blood with an IC50 of nm of the of CP-481,715 in the antagonist properties of we the of multiple of CP-481,715 on the of CCL3 to CD11b in human whole in of CP-481,715 a of the CCL3 of competitive The of CP-481,715 to the CCL3 to be nm). of these data by a of is different from J. PubMed Scopus Google Scholar), and a of of CP-481,715 on in its therapeutic potential and its ability to CCR1 in a we the ability of CP-481,715 to inhibit monocyte chemotaxis induced by synovial of synovial fluid were from rheumatoid arthritis subjects disease of and were agents and synovial fluid in vitro monocyte chemotactic activity as demonstrated using be with neutralizing antibodies to macrophage inflammatory and CP-481,715 90% of this monocyte chemotactic activity in 11/15 of the The of CP-481,715 to inhibit chemotaxis and from to depending on the These studies illustrate the ability of CP-481,715 to inhibit monocyte chemotaxis induced by its ability to inhibit the effects of CCR1 in their and the therapeutic potential of CP-481,715 in rheumatoid of synovial chemotaxis of monocytes by in a of CP-481,715 on CCL3 and by have been in the pathogenesis of rheumatoid arthritis. In synovial fluid levels were in the of CCL5 has been to monocyte we the ability of CP-481,715 to inhibit this mononuclear cells with nm CCL5 induced by CP-481,715 (IC50 = nm), that the ability of CCL5 to (12Klier C.M. Nelson E.L. Cohen C.D. Horuk R. Schlondorff D. Nelson P.J. Biol. Chem. Hoppe-Seyler. 2001; 382: 1405-1410Crossref PubMed Scopus (47) Google Scholar) induced by mononuclear by that its effects in by stimulating CCR1 Although it is to to the of CP-481,715 also of the induced by synovial fluid on human cells These studies that CCR1 play a role in in rheumatoid arthritis and that a CCR1 antagonist this describe the pharmacological of a novel CCR1 antagonist that has potential for the of inflammatory diseases as rheumatoid arthritis. CP-481,715 binds to human CCR1, and blocks the ability of CCR1 to calcium cell migration, and monocyte protease CP-481,715 is as compared with other small molecular weight chemokine receptor antagonists 2000; Google Scholar, R. H.P. Med. Rev. 2000; PubMed Scopus Google Scholar, M. C. M. H.P. K. S. A. B. K. E. J. H. B. R. D. L. S. R.M. Hesselgesser J. Perez H.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (178) Google Scholar, T. F. B. S. D. M. J.M. J. Jr., D. R. K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) in that it a a to to in the receptor (e.g. In of its therapeutic CP-481,715 retains activity (e.g. whole and is to chemotaxis induced by CCR1 present in a fluid (e.g. rheumatoid arthritis synovial that and function can be by their of agonist and antagonist antagonist, studies that CP-481,715 behaves as a and competitive antagonist for human CCR1. CP-481,715 lacks intrinsic agonist activity as by its of effects on calcium Furthermore, CP-481,715 is an as by the of effects on CP-481,715 the ability of several CCR1 to stimulate multiple on CCR1-transfected cells and on cells expressing CCR1 human Furthermore, the of CP-481,715 to inhibit activity directly proportional to the of agonist of whole blood a of to a of to it as a competitive antagonist J. PubMed Scopus Google Scholar). The ability of CP-481,715 to inhibit cell activity by CCR1 to be to its receptor and through effects on cell function through effects on CCR1 CP-481,715 the receptor at to that for of calcium and CD11b CP-481,715 also on calcium mobilization and chemotaxis induced by in the cell In CP-481,715 directly on CCR1 as supported by its of on and calcium mobilization on we that CP-481,715 on cells and its effects as a CCR1 antagonist and through of activity signaling CCR1 antagonist has the potential to several in the inflammatory it the of cells to the during an inflammatory by inhibiting CD11b This is a to cell C.M. K. Blood. 2002; PubMed Scopus Google Scholar). CCR1 the of cells into tissue as by the ability of CP-481,715 to the chemotaxis of monocytes in to CCR1 as well as in inflammatory a CCR1 antagonist also directly decrease tissue damage by at inflammatory sites as by the ability of CP-481,715 to monocyte This of observed in to CCL5 but also to CCL5 in that is through the of CCR1 the role of in the pathogenesis of inflammatory diseases as rheumatoid arthritis (3Dayer J.M. Joint, Bone, Spine: Revue du Rhumatisme. 2002; 69: 123-132Crossref PubMed Scopus (66) Google Scholar, 4Meyer O. Presse Medicale. 2000; 29: 463-468PubMed Google Scholar), this to the potential therapeutic of Although a of chemokines have been to be expressed in the synovial fluid of rheumatoid arthritis the chemokines that inflammation is their levels can to the of synovial T. Buus A. Moller B.K. Stengaard-Pedersen K. Scand. J. Rheumatol. 2000; 29: 216-221Crossref PubMed Scopus (21) Google Scholar, 20Violin M.V. Shah M.R. Tokuhira M. Haines G.K. Woods J.M. Koch A.E. Clin. Immunol. Immunopathol. 1998; 89: 44-53Crossref PubMed Scopus (117) Google Scholar, 21al-Mughales J. Blyth T.H. Hunter J.A. Wilkinson P.C. Clin. Exp. Immunol. 1996; 106: 230-236Crossref PubMed Scopus (59) Google Scholar). Furthermore, of the chemotactic for cell infiltration are on their levels and the of the receptors on peripheral studies have demonstrated that the in vitro monocyte chemotactic activity of synovial fluid be to using neutralizing antibodies to CCL3 in CCL5 (17Katrib A. Tak P.P. Bertouch J.V. Cuello C. McNeil H.P. Smeets T.J.M. Kraan M.C. Youssef P.P. Rheumatology. 2001; 40: 988-994Crossref PubMed Scopus (69) Google Scholar, 18Koch A.E. Kunkel S.L. Harlow L.A. Mazarakis D.D. Haines G.K. Burdick M.D. Pope R.M. Strieter R.M. J. Clin. Invest. 1994; 93: 921-928Crossref PubMed Google Scholar, 19Ellingsen T. Buus A. Moller B.K. Stengaard-Pedersen K. Scand. J. Rheumatol. 2000; 29: 216-221Crossref PubMed Scopus (21) Google Scholar, 20Violin M.V. Shah M.R. Tokuhira M. Haines G.K. Woods J.M. Koch A.E. Clin. Immunol. Immunopathol. 1998; 89: 44-53Crossref PubMed Scopus (117) Google Scholar, 21al-Mughales J. Blyth T.H. Hunter J.A. Wilkinson P.C. Clin. Exp. Immunol. 1996; 106: 230-236Crossref PubMed Scopus (59) Google Scholar). However, observed in these and receptor CCL3 and CCL5 can with CCR1 these studies the of other CCR1 (e.g. and studies that a of monocyte chemotactic have been in synovial fluid T. K. S. K. S. J. Immunol. 2000; PubMed Scopus Google Scholar), (17Katrib A. Tak P.P. Bertouch J.V. Cuello C. McNeil H.P. Smeets T.J.M. Kraan M.C. Youssef P.P. Rheumatology. 2001; 40: 988-994Crossref PubMed Scopus (69) Google the ability of CP-481,715 to inhibit 90% of the chemotactic that CCR1 on monocytes and CCR1 in synovial fluid the The of CP-481,715 to inhibit synovial fluid chemotaxis Although the for this of is a is that levels of CCR1 are present in the of CP-481,715 to inhibit monocyte chemotaxis is directly on the of agonist This is to because to levels of CCR1 are is that present in the synovial fluid the of CP-481,715 to inhibit However, we this is CP-481,715 retains activity in human whole to the agonist properties of the CCR1 in synovial CCR1 have been to have agonist activity by as have the of CP-481,715 to inhibit activity P. P. S. E. J. Blood. 2000; PubMed Google Scholar). studies be to these the ability of CP-481,715 to inhibit chemotaxis induced by inflammatory fluid its potential in and the of the that be to inhibit cell studies a novel and selective CCR1 antagonist. The ability of CP-481,715 to several by CCR1 and to in whole blood its Furthermore, studies effects of CCR1 including its role on the monocyte chemotactic activity in synovial fluid and its effects on matrix metalloproteinase These studies the that CP-481,715 be beneficial for the of rheumatoid arthritis and other inflammatory diseases in CCR1 has been J.B. A.J. R. H.L. Eur. J. Immunol. 2000; PubMed Scopus Google Scholar, J.A. B. J. Clin. Invest. 2000; PubMed Scopus Google Scholar).
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