A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

BMC Immunology

Volumn 13, Issue , 2012, Pages

  Jenh, Chung Her ^a   Cox, Mary Ann ^a   Cui, Long ^a   Reich, Eva Pia ^a   Sullivan, Lee ^a   Chen, Shu Cheng ^a   Kinsley, David ^a   Qian, Shiguang ^b,c   Kim, Seong Heon ^a   Rosenblum, Stuart ^a   Kozlowski, Joseph ^a   Fine, Jay S ^a,c,d   Zavodny, Paul J ^a   Lundell, Daniel ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^c LERNER RESEARCH INSTITUTE   (United States)

^d BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA INTERFERON; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR3; CHEMOTAXIS INHIBITOR; CXCL11 CHEMOKINE; CYCLOSPORIN; GAMMA INTERFERON INDUCIBLE PROTEIN 10; SCH 546738; UNCLASSIFIED DRUG; PIPERAZINE DERIVATIVE; PROTEIN BINDING; PYRAZINAMIDE;

ALLERGIC ENCEPHALOMYELITIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; AUTOIMMUNE DISEASE; BINDING AFFINITY; CARDIAC GRAFT REJECTION; CHEMOTAXIS; CONTROLLED STUDY; DISEASE SEVERITY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG SELECTIVITY; ENGRAFTMENT; FEMALE; HEART TRANSPLANTATION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; RAT; RHEUMATOID ARTHRITIS; T LYMPHOCYTE; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; ARTHRITIS, EXPERIMENTAL; ARTHRITIS, RHEUMATOID; AUTOIMMUNE DISEASES; DISEASE MODEL; DRUG EFFECTS; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; GRAFT REJECTION; GRAFT SURVIVAL; IMMUNOLOGY; MULTIPLE SCLEROSIS; NEUTROPHIL CHEMOTAXIS; RADIOASSAY;

ANIMALS; ARTHRITIS, EXPERIMENTAL; ARTHRITIS, RHEUMATOID; AUTOIMMUNE DISEASES; CHEMOTAXIS, LEUKOCYTE; DISEASE MODELS, ANIMAL; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; GRAFT REJECTION; GRAFT SURVIVAL; HEART TRANSPLANTATION; HUMANS; IN VITRO TECHNIQUES; MICE; MULTIPLE SCLEROSIS; PIPERAZINES; PROTEIN BINDING; PYRAZINAMIDE; RADIOLIGAND ASSAY; RATS; RECEPTORS, CXCR3; T-LYMPHOCYTES;

EID: 84855492353     PISSN: None     EISSN: 14712172     Source Type: Journal    
DOI: 10.1186/10.1186/1471-2172-13-2     Document Type: Article

References (59)

1. Rollins B. Chemokines. Blood 1997, 90:909-928.
2. Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol 1997, 15:675-705.
3. Schall TJ, Bacon KB. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immuno 1994, 6:865-873.
4. Hedrick J, Zlotnik A. Chemokines and lymphocyte biology. Curr Opin Immunol 1996, 8:343-347.
5. Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis T, Baggiolini M, Moser B. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 1996, 184:963-969.
6. Farber JM. Mig and IP-10: CXC chemokines that target lymphocytes. J Leukocyte Bio 1997, 61:246-257.
7. Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, Gladue RP, Lin W, Boyd JG, Moser B, Wood DE, Sahagan BG, Neote K. Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med 1998, 187:2009-2021.
8. Loetscher M, Loetscher P, Brass N, Meese E, Moser B. Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 1998, 28:3696-3705.
9. Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000, 52:145-176.
10. Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J Exp Med 2000, 192:1515-1520.
11. Agostini C, Calabrese F, Rea F, Facco M, Tosoni A, Loy M, Binotto G, Valente M, Trentin L, Semenzato G. Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection. Am J Pathol 2001, 158:1703-1711.
12. Melter M, Exeni A, Reinders ME, Fang JC, McMahon G, Ganz P, Hancock WW, Briscoe DM. Expression of the chemokine receptor CXCR3 and its ligand IP-10 during human cardiac allograft rejection. Circulation 2001, 104:2558-2564.
13. Hancock WW, Wang L, Ye Q, Han R, Lee I. Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. Curr Opin Immunol 2003, 15:479-486.
14. Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Machay CR. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 1998, 101:746-754.
15. Wedderburn LR, Robinson N, Patel A, Varsani H, Woo P. Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum 2000, 43:765-774.
16. Patel DD, Zachariah JP, Whichard LP. CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol 2001, 98:39-45.
17. Katschke KJ, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 2001, 44:1022-1032.
18. Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 1999, 103:807-815.
19. Balashov KE, Rottman JB, Weiner HL, Hancock WW. CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 1999, 96:6873-6878.
20. Flier J, Boorsma DM, van Beek PJ, Nieboer C, Stoof TJ, Willemze R, Tensen CP. Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol 2001, 194:398-405.
21. Medina J. Presented at the 29th National Medicinal Chemistry Symposium (Madison, Wisconsin), June 27-July 1. 2004,
22. Heise CE, Pahuja A, Hudson SC, Mistry MS, Putnam AL, Gross MM, Gottlieb PA, Wade WS, Kiankarimi M, Schwarz D, Crowe P, Zlotnik A, Alleva DG. Pharmacological characterization of CXC chemokine receptor 3 ligands and a small molecule antagonist. J Pharmacol Exp Ther 2005, 313:1263-1271.
23. Storelli S, Verdijk P, Verzijl D, Timmerman H, van de Stolpe AC, Tensen CP, Smit MJ, De Esch IJ, Leurs R. Synthesis and structure-activity relationship of 3-phenyl-3H-quinazolin-4-one derivatives as CXCR3 chemokine receptor antagonists. Bioorg Med Chem Lett 2005, 15:2910-2913.
24. Allen DR, Bolt A, Chapman GA, Knight RL, Meissner JW, Owen DA, Watson RJ. Identification and structure-activity relationships of 1-aryl-3-piperidin-4-ylurea derivatives as CXCR3 receptor antagonists. Bioorg Med Chem Lett 2007, 17:697-701.
25. Johnson M, Li AR, Liu J, Fu Z, Zhu L, Miao S, Wang X, Xu Q, Huang A, Marcus A, Xu F, Ebsworth K, Sablan E, Danao J, Kumer J, Dairaghi D, Lawrence C, Sullivan T, Tonn G, Schall T, Collins T, Medina J. Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. Bioorg Med Chem Lett 2007, 17:3339-3343.
26. Watson RJ, Allen DR, Birch HL, Chapman GA, Hannah DR, Knight RL, Meissner JW, Owen DA, Thomas EJ. Development of CXCR3 antagonists. Part 2: Identification of 2-amino(4-piperidinyl)azoles as potent CXCR3 antagonists. Bioorg Med Chem Lett 2007, 17:6806-6810.
27. Hayes ME, Wallace GA, Grongsaard P, Bischoff A, George DM, Miao W, McPherson MJ, Stoffel RH, Green DW, Roth GP. Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3. Bioorg Med Chem Lett 2008, 18:1573-1576.
28. Du X, Gustin DJ, Chen X, Duquette J, McGee LR, Wang Z, Ebsworth K, Henne K, Lemon B, Ma J, Miao S, Sabalan E, Sullivan TJ, Tonn G, Collins TL, Medina JC. Imidazo-pyrazine derivatives as potent CXCR3 antagonists. Bioorg Med Chem Lett 2009, 19:5200-5204.
29. Liu J, Fu Z, Li AR, Johnson M, Zhu L, Marcus A, Danao J, Sullivan T, Tonn G, Collins T, Medina J. Optimization of a series of quinazolinone-derived antagonists of CXCR3. Bioorg Med Chem Lett 2009, 19:5114-5118.
30. Crosignani S, Missotten M, Cleva C, Dondi R, Ratinaud Y, Humbert Y, Mandal AB, Bombrun A, Power C, Chollet A, Proudfoot A. Discovery of a novel series of CXCR3 antagonists. Bioorg Med Chem Lett 2010, 20:3614-3617.
31. van Wanrooij EJ, de Jager SC, van Es T, de Vos P, Birch HL, Owen DA, Watson RJ, Biessen EA, Chapman GA, van Berkel TJ, Kuiper J. CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptordeficient mice. Arterioscler Thromb Vasc Biol 2008, 28:251-257.
32. Rosenblum JM, Zhang QW, Siu G, Collins TL, Sullivan T, Dairaghi DJ, Medina JC, Fairchild RL. CXCR3 antagonism impairs the development of donorreactive, IFN-gamma-producing effectors and prolongs allograft survival. Transplantation 2009, 87:360-369.
33. Cambien B, Karimdjee BF, Richard-Fiardo P, Bziouech H, Barthel R, Millet MA, Martini V, Birnbaum D, Scoazec JY, Abello J, Al Saati T, Johnson MG, Sullivan TJ, Medina JC, Collins TL, Schmid-Alliana A, Schmid-Antomarchi H. Organspecific inhibition of metastatic colon carcinoma by CXCR3 antagonism. Br J Cancer 2009, 100:1755-1764.
34. Walser TC, Rifat S, Ma X, Kundu N, Ward C, Goloubeva O, Johnson MG, Medina JC, Collins TL, Fulton AM. Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res 2006, 66:7701-7707.
35. Kim SH, Anilkumara GN, Zawacki LG, Zeng Q, Yang DY, Shao Y, Dong G, Xu X, Yu W, Jiang Y, Jenh CH, Hall JW, Carroll CD, Hobbs DW, Rosenblum SB, Kozlowski JA, McGuinness BF, Shankara BB, Shih NY. III. Identification of Novel CXCR3 Chemokine Receptor Antagonists with a Pyrazinyl-Piperazinyl-Piperidine Scaffold. Bioorg Med Chem Lett 2011, 21:6982-6986.
36. Soto H, Wang W, Strieter RM, Copeland NG, Gilbert DJ, Jenkins NA, Hedrick J, Zlotnik A. The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proc Natl Acad Sci USA 1998, 95:8205-8210.
37. Wang X, Li X, Schmidt DB, Foley JJ, Barone FC, Ames RS, Sarau HM. Identification and molecular characterization of rat CXCR3: receptor expression and interferon-inducible protein-10 binding are increased in focal stroke. Mol Pharmacol 2000, 57:1190-1198.
38. Jenh CH, Cox MA, Kaminski H, Zhang M, Byrnes H, Fine J, Lundell D, Chou CC, Narula SK, Zavodny PJ. Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3:human 6Ckine is not a ligand for the human or mouse CXCR3 receptors. J Immunol 1999, 162:3765-3769.
39. Jenh CH, Cox MA, Hipkin W, Lu T, Pugliese-Sivo C, Gonsiorek W, Chou CC, Narula SK, Zavodny PJ. Human B cell-attracting chemokine 1 (BCA-1;CXCL13) is an agonist for the human CXCR3 receptor. Cytokine 2001, 15:113-121.
40. Campbell IK, Hamilton JA, Wicks IP. Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis. Eur J Immunol 2000, 30:1568-1575.
41. Mankin HJ, Dorfman H, Lippiello L, Zarins A. Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am 1971, 53:523-537.
42. Ono K, Lindsey ES. Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 1969, 57:225-229.
43. McGuinness BF, Carroll CD, Zawacki LG, Dong G, Yang C, Hobbs DW, Jacob-Samuel B, Hall JW, Jenh CH, Kozlowski JA, Anilkumar GN, Rosenblum SB. Novel CXCR3 antagonists with a piperazinyl-piperidine core. Bioorg Med Chem Lett 2009, 19:5205-5208.
44. Medarex Announces Primary Endpoint Achieved in MDX-1100 Anti-IP-10 Antibody Phase 2 Trial for Rheumatoid Arthritis. , http://www.fiercebiotech.com/press-releases/medarex-announces-primary-endpoint-achieved-mdx-1100-anti-ip-10-antibody-phase-2-tria
45. Wijtmans M, Verzijl D, Leurs R, de Esch IJ, Smit MJ. Towards small-molecule CXCR3 ligands with clinical potential. ChemMedChem 2008, 3:861-872.
46. Mohan K, Issekutz TB. Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis. J Immunol 2007, 179:8463-8469.
47. Liu L, Callahan MK, Huang D, Ransohoff RM. Chemokine receptor CXCR3: an unexpected enigma. Curr Top Dev Biol 2005, 68:149-181.
48. Byrne FR, Winters A, Brankow D, Hu S, Juan T, Steavenson S, Doellgast G, Kuchimanchi K, Brown H, Anderson S, Smelt S, Sullivan T, Alcorn D, Tocker J, Dean C, Macmaster J, Kirchner J, Buys J, Manoukian R, Jiao E, Zou X, Campanella GS, Siu G. An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation. Autoimmunity 2009, 42:171-182.
49. Liu L, Huang D, Matsui M, He TT, Hu T, Demartino J, Lu B, Gerard C, Ransohoff RM. Severe disease, unaltered leukocyte migration, and reduced IFN-gamma production in CXCR3-/- mice with experimental autoimmune encephalomyelitis. J Immunol 2006, 176:4399-4409.
50. Müller M, Carter SL, Hofer MJ, Manders P, Getts DR, Getts MT, Dreykluft A, Lu B, Gerard C, King NJ, Campbell IL. CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system. J Immunol 2007, 179:2774-2786.
51. Müller M, Carter S, Hofer MJ, Campbell IL. Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity--a tale of conflict and conundrum. Neuropathol Appl Neurobiol 2010, 36:368-387.
52. Ni J, Zhu YN, Zhong XG, Ding Y, Hou LF, Tong XK, Tang W, Ono S, Yang YF, Zuo JP. The chemokine receptor antagonist, TAK-779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function. Br J Pharmacol 2009, 158:2046-2056.
53. Hancock WW, Gao W, Csizmadia V, Faia KL, Shemmeri N, Luster AD. Donorderived IP-10 initiates development of acute allograft rejection. J Exp Med 2001, 193:975-980.
54. Kwun J, Hazinedaroglu SM, Schadde E, Kayaoglu HA, Fechner J, Hu HZ, Roenneburg D, Torrealba J, Shiao L, Hong X, Peng R, Szewczyk JW, Sullivan KA, DeMartino J, Knechtle SJ. Unaltered graft survival and intragraft lymphocytes infiltration in the cardiac allograft of Cxcr3-/- mouse recipients. Am J Transplant 2008, 8:1593-1603.
55. Zerwes HG, Li J, Kovarik J, Streiff M, Hofmann M, Roth L, Luyten M, Pally C, Loewe RP, Wieczorek G, Bänteli R, Thoma G, Luckow B. The chemokine receptor Cxcr3 is not essential for acute cardiac allograft rejection in mice and rats. Am J Transplant 2008, 8:1604-1613.
56. Uppaluri R, Sheehan KC, Wang L, Bui JD, Brotman JJ, Lu B, Gerard C, Hancock WW, Schreiber RD. Prolongation of cardiac and islet allograft survival by a blocking hamster anti-mouse CXCR3 monoclonal antibody. Transplantation 2008, 86:137-147.
57. Bastani S, Sherman W, Schnickel GT, Hsieh GR, Bhatia R, Fishbein MC, Ardehali A. Chemokine receptor blockade with a synthetic nonpeptide compound attenuates cardiac allograft vasculopathy. Transplantation 2009, 88:995-1001.
58. Rosenblum JM, Zhang QW, Siu G, Collins TL, Sullivan T, Dairaghi DJ, Medina JC, Fairchild RL. CXCR3 antagonism impairs the development of donorreactive, IFN-gamma-producing effectors and prolongs allograft survival. Transplantation 2009, 87:360-369.
59. Bowdish ME, Barr ML, Quardt SM, et al. Evaluation of an oral CXCR3 antagonist in a rat model of acute cardiac allografts rejection. Am J Transplant 2003, 3(Suppl 5):4-62.