Chemokine receptor antagonists

Journal of Medicinal Chemistry

Volumn 55, Issue 22, 2012, Pages 9363-9392

  Pease, James ^a   Horuk, Richard ^b  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 BROMOPHENYL) 3 (2 HYDROXY 4 NITROPHENYL)UREA; 1 [5 CHLORO 2 [2 [4 (4 FLUOROBENZYL) 2 METHYL 1 PIPERAZINYL] 2 OXOETHOXY]PHENYL]UREA; 1,5 ANHYDRO 2,3 DIDEOXY 3 [[3 [[7,8 DIHYDRO 3 (TRIFLUOROMETHYL) 1,6 NAPHTHYRIDIN 6(5H) YL]CARBONYL] 3 ISOPROPYLCYCLOPENTYL]AMINO] 4 O METHYLPENTITOL; 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; AMG 487; APLAVIROC; ASM 8; AZD 3778; AZD 4818; AZD 5672; BKT 140; BMS 193884; BMS 639623; BMS 741672; C 4462; C 6448; CCX 140; CCX 354; CCX 915; CENICRIVIROC; CHEMOKINE RECEPTOR; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CXCR4; CP 481715; DPC 168; ELUBRIXIN; G PROTEIN COUPLED RECEPTOR; GSK 2239633; GSK 766864; GSK 766994; GW 873410; HGS 004; INCB 10820; INCB 3284; INCB 8696; INCB 9471; JNJ 17166864; MARAVIROC; MDX 1338; MLN 1202; MLN 3701; MLN 3897; MOGAMULIZUMAB; MRL 677; N [2 [[1 [4 (1,3 BENZODIOXOL 5 YL) 4 HYDROXYCYCLOHEXYL] 4 ETHOXY 3 PYRROLIDINYL]AMINO] 2 OXOETHYL] 3 (TRIFLUOROMETHYL)BENZAMIDE; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NAVARIXIN; NIBR 6145; NIBR 6465; PF 4136309; PF 4178903; PLERIXAFOR; POL 6326; PRO 140; PS 433540; QAP 642; RALTEGRAVIR; SB 728; TG 0054; UK 107543; UK 127857; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERCIRNON; VICRIVIROC; YM 344484;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ALLERGIC ASTHMA; ALLERGIC RHINITIS; ALLERGY; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; ASTHMA; ATHEROSCLEROSIS; AUTOIMMUNE DISEASE; BINDING AFFINITY; CANCER RECURRENCE; CHRONIC OBSTRUCTIVE LUNG DISEASE; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENCY; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; ENDOMETRIOSIS; HUMAN; HYPERGLYCEMIA; INFUSION RELATED REACTION; LIVER TOXICITY; MULTIPLE MYELOMA; MULTIPLE SCLEROSIS; NEUROPATHIC PAIN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PAIN; PATHOPHYSIOLOGY; PERIPHERAL T CELL LYMPHOMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN FUNCTION; PROTEIN STRUCTURE; PSORIASIS; QT PROLONGATION; RASH; REVIEW; RHEUMATOID ARTHRITIS; STRUCTURE ACTIVITY RELATION; T CELL LEUKEMIA; T CELL LYMPHOMA; UNSPECIFIED SIDE EFFECT;

ANIMALS; AUTOIMMUNE DISEASES; HUMANS; RECEPTORS, CHEMOKINE;

EID: 84869994291     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300682j     Document Type: Review

References (257)

1. Zlotnik, A.; Yoshie, O. Chemokines: a new classification system and their role in immunity Immunity 2000, 12, 121-127
2. Charo, I. F.; Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation N. Engl. J. Med. 2006, 354, 610-621
3. Viola, A.; Luster, A. D. Chemokines and their receptors: drug targets in immunity and inflammation Annu. Rev. Pharmacol. Toxicol. 2008, 48, 171-197
4. Fredriksson, R.; Lagerstrom, M. C.; Lundin, L. G.; Schioth, H. B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints Mol. Pharmacol. 2003, 63, 1256-1272
5. Murphy, P. M.; Baggiolini, M.; Charo, I. F.; Hebert, C. A.; Horuk, R.; Matsushima, K.; Miller, L. H.; Oppenheim, J. J.; Power, C. A. International Union of Pharmacology. XXII. Nomenclature for chemokine receptors Pharmacol. Rev. 2000, 52, 145-176
6. Murphy, P. M. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature Pharmacol. Rev. 2002, 54, 227-229
7. Walsh, S. J.; Rau, L. M. Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States Am. J. Public Health 2000, 90, 1463-1466
8. Stoll, J. G.; Yasothan, U. Rheumatoid arthritis market Nat. Rev. Drug Discovery 2009, 8, 693-694
9. PRWeb. Global Autoimmune Disease Therapeutics Market To Exceed US$77 Billion by 2017, According to New Report by Global Industry Analysts, Inc. http://www.prweb.com/releases/autoimmune-disease/therapeutics- drugs/prweb8957282.htm.
10. MacArthur, R. D.; Novak, R. M. Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents Clin. Infect. Dis. 2008, 47, 236-241
11. De Clercq, E. The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil) Biochem. Pharmacol. 2008, 77, 1655-1664
12. Brave, M.; Farrell, A.; Ching Lin, S.; Ocheltree, T.; Pope Miksinski, S.; Lee, S. L.; Saber, H.; Fourie, J.; Tornoe, C.; Booth, B.; Yuan, W.; He, K.; Justice, R.; Pazdur, R. FDA review summary: Mozobil in combination with granulocyte colony-stimulating factor to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation Oncology 2010, 78, 282-288
13. Congreve, M.; Langmead, C.; Marshall, F. H. The use of GPCR structures in drug design Adv. Pharmacol. 2011, 62, 1-36
14. Choi, W. T.; Duggineni, S.; Xu, Y.; Huang, Z.; An, J. Drug discovery research targeting the CXC chemokine receptor 4 (CXCR4) J. Med. Chem. 2012, 55, 977-994
15. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: a G protein-coupled receptor Science 2000, 289, 739-745
16. Cherezov, V.; Rosenbaum, D. M.; Hanson, M. A.; Rasmussen, S. G.; Thian, F. S.; Kobilka, T. S.; Choi, H. J.; Kuhn, P.; Weis, W. I.; Kobilka, B. K.; Stevens, R. C. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor Science 2007, 318, 1258-1265
17. Wu, B.; Chien, E. Y.; Mol, C. D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F. C.; Hamel, D. J.; Kuhn, P.; Handel, T. M.; Cherezov, V.; Stevens, R. C. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists Science 2010, 330, 1066-1071
18. Lefkowitz, R. J.; Shenoy, S. K. Transduction of receptor signals by beta-arrestins Science 2005, 308, 512-517
19. Schwartz, T. W.; Frimurer, T. M.; Holst, B.; Rosenkilde, M. M.; Elling, C. E. Molecular mechanism of 7TM receptor activation - a global toggle switch model Annu. Rev. Pharmacol. Toxicol. 2006, 46, 481-519
20. Monteclaro, F. S.; Charo, I. F. The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1alpha receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation J. Biol. Chem. 1996, 271, 19084-19092
21. Pease, J. E.; Wang, J.; Ponath, P. D.; Murphy, P. M. The N-terminal extracellular segments of the chemokine receptors CCR1 and CCR3 are determinants for MIP-1alpha and eotaxin binding, respectively, but a second domain is essential for efficient receptor activation J. Biol. Chem. 1998, 273, 19972-19976
22. Farzan, M.; Mirzabekov, T.; Kolchinsky, P.; Wyatt, R.; Cayabyab, M.; Gerard, N. P.; Gerard, C.; Sodroski, J.; Choe, H. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry Cell 1999, 96, 667-676
23. 2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines J. Exp. Med. 2001, 194, 1661-1673
24. Rosenkilde, M. M.; Benned-Jensen, T.; Frimurer, T. M.; Schwartz, T. W. The minor binding pocket: a major player in 7TM receptor activation Trends Pharmacol. Sci. 2010, 31, 567-574
25. Van Damme, J.; Struyf, S.; Wuyts, A.; Van Coillie, E.; Menten, P.; Schols, D.; Sozzani, S.; De Meester, I.; Proost, P. The role of CD26/DPP IV in chemokine processing Chem. Immunol. 1999, 72, 42-56
26. Proudfoot, A. E.; Buser, R.; Borlat, F.; Alouani, S.; Soler, D.; Offord, R. E.; Schroder, J. M.; Power, C. A.; Wells, T. N. Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors J. Biol. Chem. 1999, 274, 32478-32485
27. Wise, E. L.; Duchesnes, C.; da Fonseca, P. C.; Allen, R. A.; Williams, T. J.; Pease, J. E. Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation J. Biol. Chem. 2007, 282, 27935-27943
28. Nedjai, B.; Li, H.; Stroke, I. L.; Wise, E. L.; Webb, M. L.; Merritt, J. R.; Henderson, I.; Klon, A. E.; Cole, A. G.; Horuk, R.; Vaidehi, N.; Pease, J. E. Small-molecule chemokine mimetics suggest a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3 Br. J. Pharmacol. 2011, 166, 912-923
29. Weathington, N. M.; van Houwelingen, A. H.; Noerager, B. D.; Jackson, P. L.; Kraneveld, A. D.; Galin, F. S.; Folkerts, G.; Nijkamp, F. P.; Blalock, J. E. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation Nat. Med. 2006, 12, 317-323
30. Andrews, G.; Jones, C.; Wreggett, K. A. An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein-coupled receptors CCR4 and CCR5 Mol. Pharmacol. 2008, 73, 855-867
31. Feng, G. J.; Kellett, E.; Scorer, C. A.; Wilde, J.; White, J. H.; Milligan, G. Selective interactions between helix VIII of the human mu-opioid receptors and the C terminus of periplakin disrupt G protein activation J. Biol. Chem. 2003, 278, 33400-33407
32. Sobocki, P.; Pugliatti, M.; Lauer, K.; Kobelt, G. Estimation of the cost of MS in Europe: extrapolations from a multinational cost study Mult. Scler. 2007, 13, 1054-1064
33. Lassmann, H.; Bruck, W.; Lucchinetti, C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy Trends Mol. Med. 2001, 7, 115-121
34. Trebst, C.; Sorensen, T. L.; Kivisakk, P.; Cathcart, M. K.; Hesselgesser, J.; Horuk, R.; Sellebjerg, F.; Lassmann, H.; Ransohoff, R. M. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis Am. J. Pathol. 2001, 159, 1701-1710
35. Balashov, K. E.; Rottman, J. B.; Weiner, H. L.; Hancock, W. W. 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. U.S.A. 1999, 96, 6873-6878
36. McManus, C.; Berman, J. W.; Brett, F. M.; Staunton, H.; Farrell, M.; Brosnan, C. F. MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study J. Neuroimmunol. 1998, 86, 20-29
37. Steinman, L.; Zamvil, S. S. Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis Trends Immunol. 2005, 26, 565-571
38. Koch, A. E.; Kunkel, S. E.; Harlow, S. E.; Mazarakis, D. D.; Haines, G. K.; Burdick, M. D.; Pope, R. M.; Strieter, R. M. Macrophage inflammatory protein-1a. A novel chemotactic cytokine for macrophages in rheumatoid arthritis J. Clin. Invest. 1994, 93, 921-928
39. Macchioni, P.; Boiardi, L.; Meliconi, R.; Pulsatelli, L.; Maldini, M. C.; Ruggeri, R.; Facchini, A.; Salvarani, C. Serum chemokines in patients with psoriatic arthritis treated with cyclosporin A J. Rheumatol. 1998, 25, 320-325
40. Kasama, T.; Strieter, R. M.; Lukacs, N. W.; Lincoln, P. M.; Burdick, M. D.; Kunkel, S. L. Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis J. Clin. Invest. 1995, 95, 2868-2876
41. Szekanecz, Z.; Szucs, G.; Szanto, S.; Koch, A. E. Chemokines in rheumatic diseases Curr. Drug Targets 2006, 7, 91-102
42. Barnes, D. A.; Tse, J.; Kaufhold, M.; Owen, M.; Hesselgesser, J.; Strieter, R.; Horuk, R.; Perez, H. D. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model J. Clin. Invest. 1998, 101, 2910-2919
43. Haas, C. S.; Martinez, R. J.; Attia, N.; Haines, G. K., 3rd; Campbell, P. L.; Koch, A. E. Chemokine receptor expression in rat adjuvant-induced arthritis Arthritis Rheum. 2005, 52, 3718-3730
44. Haringman, J. J.; Smeets, T. J.; Reinders-Blankert, P.; Tak, P. P. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis Ann. Rheum. Dis. 2006, 65, 294-300
45. Amat, M.; Benjamim, C. F.; Williams, L. M.; Prats, N.; Terricabras, E.; Beleta, J.; Kunkel, S. L.; Godessart, N. Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo Br. J. Pharmacol. 2006, 149, 666-675
46. Haringman, J. J.; Kraan, M. C.; Smeets, T. J.; Zwinderman, K. H.; Tak, P. P. Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis Ann. Rheum. Dis. 2003, 62, 715-721
47. Koch, A. E.; Kunkel, S. L.; Harlow, L. A.; Johnson, B.; Evanoff, H. L.; Haines, G. K.; Burdick, M. D.; Pope, R. M.; Strieter, R. M. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis J. Clin. Invest. 1992, 90, 772-779
48. Villiger, P. M.; Terkeltaub, R.; Lotz, M. Monocyte chemoattractant protein-1 (MCP-1) expression in human articular cartilage. Induction by peptide regulatory factors and differential effects of dexamethasone and retinoic acid J. Clin. Invest. 1992, 90, 488-496
49. Katschke, K. J., Jr.; Rottman, J. B.; Ruth, J. H.; Qin, S.; Wu, L.; LaRosa, G.; Ponath, P.; Park, C. C.; Pope, R. M.; Koch, A. E. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis Arthritis Rheum. 2001, 44, 1022-1032
50. Koch, A. E.; Kunkel, S. L.; Burrows, J. C.; Evanhoff, H. L.; Haines, G. K.; Pope, R. M.; Strieter, R. M. Synovial tissue macrophage as a source of the chemotactic cytokine IL-8 J. Immunol. 1991, 147, 2187-2195
51. Koch, A. E.; Kunkel, S. L.; Shah, M. R.; Hosaka, S.; Halloran, M. M.; Haines, G. K.; Burdick, M. D.; Pope, R. M.; Strieter, R. M. Growth-related gene product alpha. A chemotactic cytokine for neutrophils in rheumatoid arthritis J. Immunol. 1995, 155, 3660-3666
52. Patel, D. D.; Zachariah, J. P.; Whichard, L. P. CXCR3 and CCR5 ligands in rheumatoid arthritis synovium Clin. Immunol. 2001, 98, 39-45
53. Kim, C. H.; Kunkel, E. J.; Boisvert, J.; Johnston, B.; Campbell, J. J.; Genovese, M. C.; Greenberg, H. B.; Butcher, E. C. Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential J. Clin. Invest. 2001, 107, 595-601
54. Kay, A. B.; Phipps, S.; Robinson, D. S. A role for eosinophils in airway remodelling in asthma Trends Immunol. 2004, 25, 477-482
55. Toda, M.; Dawson, M.; Nakamura, T.; Munro, P. M.; Richardson, R. M.; Bailly, M.; Ono, S. J. Impact of engagement of FcepsilonRI and CC chemokine receptor 1 on mast cell activation and motility J. Biol. Chem. 2004, 279, 48443-48448
56. Miyazaki, D.; Nakamura, T.; Toda, M.; Cheung-Chau, K. W.; Richardson, R. M.; Ono, S. J. Macrophage inflammatory protein-1alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions J. Clin. Invest. 2005, 115, 434-442
57. Power, C. A.; Church, D. J.; Meyer, A.; Alouani, S.; Proudfoot, A. E.; Clark-Lewis, I.; Sozzani, S.; Mantovani, A.; Wells, T. N. Cloning and characterization of a specific receptor for the novel CC chemokine MIP-3alpha from lung dendritic cells J. Exp. Med. 1997, 186, 825-835
58. Pilette, C.; Francis, J. N.; Till, S. J.; Durham, S. R. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge Eur. Respir. J. 2004, 23, 876-884
59. Panina-Bordignon, P.; Papi, A.; Mariani, M.; Di Lucia, P.; Casoni, G.; Bellettato, C.; Buonsanti, C.; Miotto, D.; Mapp, C.; Villa, A.; Arrigoni, G.; Fabbri, L. M.; Sinigaglia, F. The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics J. Clin. Invest. 2001, 107, 1357-1364
60. Mutalithas, K.; Guillen, C.; Raport, C.; Kolbeck, R.; Soler, D.; Brightling, C. E.; Pavord, I. D.; Wardlaw, A. J. Expression of CCR8 is increased in asthma Clin. Exp. Allergy 2010, 40, 1175-1185
61. Ying, S.; Robinson, D. S.; Meng, Q.; Rottman, J.; Kennedy, R.; Ringler, D. J.; Mackay, C. R.; Daugherty, B. L.; Springer, M. S.; Durham, S. R.; Williams, T. J.; Kay, A. B. Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant co-localization of eotaxin mRNA to bronchial epithelial and endothelial cells Eur. J. Immunol. 1997, 27, 3507-3516
62. Ying, S.; Meng, Q.; Zeibecoglou, K.; Robinson, D. S.; Macfarlane, A.; Humbert, M.; Kay, A. B. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (intrinsic) asthmatics J. Immunol. 1999, 163, 6321-6329
63. Yamada, H.; Yamaguchi, M.; Yamamoto, K.; Nakajima, T.; Hirai, K.; Morita, Y.; Sano, Y. Eotaxin in induced sputum of asthmatics: relationship with eosinophils and eosinophil cationic protein in sputum Allergy 2000, 55, 392-397
64. Sallusto, F.; Mackay, C. R.; Lanzavecchia, A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells Science 1997, 277, 2005-2007
65. Mantovani, A. The chemokine system: redundancy for robust outputs Immunol. Today 1999, 20, 254-257
66. Gao, W.; Topham, P. S.; King, J. A.; Smiley, S. T.; Csizmadia, V.; Lu, B.; Gerard, C. J.; Hancock, W. W. Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection J. Clin. Invest. 2000, 105, 35-44
67. Rottman, J. B.; Slavin, A. J.; Silva, R.; Weiner, H. L.; Gerard, C. G.; Hancock, W. W. Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent Eur. J. Immunol. 2000, 30, 2372-2377
68. Potteaux, S.; Combadiere, C.; Esposito, B.; Casanova, S.; Merval, R.; Ardouin, P.; Gao, J. L.; Murphy, P. M.; Tedgui, A.; Mallat, Z. Chemokine receptor CCR1 disruption in bone marrow cells enhances atherosclerotic lesion development and inflammation in mice Mol. Med. 2005, 11, 16-20
69. Boring, L.; Gosling, J.; Chensue, S. W.; Kunkel, S. L.; Farese, R. V., Jr.; Broxmeyer, H. E.; Charo, I. F. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice J. Clin. Invest. 1997, 100, 2552-2561
70. Peters, W.; Dupuis, M.; Charo, I. F. A mechanism for the impaired IFN-gamma production in C-C chemokine receptor 2 (CCR2) knockout mice: role of CCR2 in linking the innate and adaptive immune responses J. Immunol. 2000, 165, 7072-7077
71. Peters, W.; Scott, H. M.; Chambers, H. F.; Flynn, J. L.; Charo, I. F.; Ernst, J. D. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7958-7963
72. Blease, K.; Mehrad, B.; Standiford, T. J.; Lukacs, N. W.; Gosling, J.; Boring, L.; Charo, I. F.; Kunkel, S. L.; Hogaboam, C. M. Enhanced pulmonary allergic responses to Aspergillus in CCR2-/- mice J. Immunol. 2000, 165, 2603-2611
73. Gonzalo, J. A.; Lloyd, C. M.; Wen, D.; Albar, J. P.; Wells, T. N.; Proudfoot, A.; Martinez, A. C.; Dorf, M.; Bjerke, T.; Coyle, A. J.; Gutierrez-Ramos, J. C. The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness J. Exp. Med. 1998, 188, 157-167
74. Collington, S. J.; Hallgren, J.; Pease, J. E.; Jones, T. G.; Rollins, B. J.; Westwick, J.; Austen, K. F.; Williams, T. J.; Gurish, M. F.; Weller, C. L. The role of the CCL2/CCR2 axis in mouse mast cell migration in vitro and in vivo J. Immunol. 2010, 184, 6114-6123
75. Boring, L.; Gosling, J.; Cleary, M.; Charo, I. F. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis Nature 1998, 394, 894-897
76. Humbles, A. A.; Lu, B.; Friend, D. S.; Okinaga, S.; Lora, J.; Al-Garawi, A.; Martin, T. R.; Gerard, N. P.; Gerard, C. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 1479-1484
77. Ma, W.; Bryce, P. J.; Humbles, A. A.; Laouini, D.; Yalcindag, A.; Alenius, H.; Friend, D. S.; Oettgen, H. C.; Gerard, C.; Geha, R. S. CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation J. Clin. Invest. 2002, 109, 621-628
78. Collington, S. J.; Westwick, J.; Williams, T. J.; Weller, C. L. The function of CCR3 on mouse bone marrow-derived mast cells in vitro Immunology 2010, 129, 115-124
79. Chvatchko, Y.; Hoogewerf, A. J.; Meyer, A.; Alouani, S.; Juillard, P.; Buser, R.; Conquet, F.; Proudfoot, A. E.; Wells, T. N.; Power, C. A. A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock J. Exp. Med. 2000, 191, 1755-1764
80. Lloyd, C. M.; Delaney, T.; Nguyen, T.; Tian, J.; Martinez, A. C.; Coyle, A. J.; Gutierrez-Ramos, J. C. CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo J. Exp. Med. 2000, 191, 265-274
81. Iellem, A.; Mariani, M.; Lang, R.; Recalde, H.; Panina-Bordignon, P.; Sinigaglia, F.; D'Ambrosio, D. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by cd4(+)cd25(+) regulatory T cells J. Exp. Med. 2001, 194, 847-854
82. Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J. L.; Zernecke, A.; Koenen, R. R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; Kooistra, T.; Fingerle-Rowson, G.; Ghezzi, P.; Kleemann, R.; McColl, S. R.; Bucala, R.; Hickey, M. J.; Weber, C. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment Nat. Med. 2007, 13, 587-596
83. Cacalano, G.; Lee, J.; Kikly, K.; Ryan, A. M.; Pitts-Meek, S.; Hultgren, B.; Wood, W. I.; Moore, M. W. Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog Science 1994, 265, 682-684
84. Fan, X.; Patera, A. C.; Pong-Kennedy, A.; Deno, G.; Gonsiorek, W.; Manfra, D. J.; Vassileva, G.; Zeng, M.; Jackson, C.; Sullivan, L.; Sharif-Rodriguez, W.; Opdenakker, G.; Van Damme, J.; Hedrick, J. A.; Lundell, D.; Lira, S. A.; Hipkin, R. W. Murine CXCR1 is a functional receptor for GCP-2/CXCL6 and interleukin-8/CXCL8 J. Biol. Chem. 2007, 282, 11658-11666
85. Abonia, J. P.; Austen, K. F.; Rollins, B. J.; Joshi, S. K.; Flavell, R. A.; Kuziel, W. A.; Koni, P. A.; Gurish, M. F. Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2 Blood 2005, 105, 4308-4313
86. Eash, K. J.; Greenbaum, A. M.; Gopalan, P. K.; Link, D. C. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow J. Clin. Invest. 2010, 120, 2423-2431
87. Del Rio, L.; Bennouna, S.; Salinas, J.; Denkers, E. Y. CXCR2 deficiency confers impaired neutrophil recruitment and increased susceptibility during Toxoplasma gondii infection J. Immunol. 2001, 167, 6503-6509
88. Tsai, H. H.; Frost, E.; To, V.; Robinson, S.; Ffrench-Constant, C.; Geertman, R.; Ransohoff, R. M.; Miller, R. H. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration Cell 2002, 110, 373-383
89. Liu, L.; Belkadi, A.; Darnall, L.; Hu, T.; Drescher, C.; Cotleur, A. C.; Padovani-Claudio, D.; He, T.; Choi, K.; Lane, T. E.; Miller, R. H.; Ransohoff, R. M. CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis Nat. Neurosci. 2010, 13, 319-326
90. Boisvert, W. A.; Santiago, R.; Curtiss, L. K.; Terkeltaub, R. A. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor- deficient mice J. Clin. Invest. 1998, 101, 353-363
91. Horuk, R. Chemokine receptor antagonists: overcoming developmental hurdles Nat. Rev. Drug Discovery 2009, 8, 23-33
92. Study To Investigate the Efficacy of a Non-Hormonal Drug against Endometriosis Associated Pelvic Pain. http://clinicaltrials.gov/ct2/show/ NCT00185341?term=CCR1&rank=1.
93. MLN 3701 Sanofi-Aventis Phase Change I, Europe. http://business.highbeam. com/436989/article-1G1-160617066/mln-3701-sanofiaventis-phase-change-europe.
94. Carson, K. G.; Jaffee, B. D.; Harriman, G. B. CCR1 Antagonists Annu. Rep. Med. Chem. 2004, 39, 149-158
95. Ng, H. P.; May, K.; Bauman, J. G.; Ghannam, A.; Islam, I.; Liang, M.; Horuk, R.; Hesselgesser, J.; Snider, R. M.; Perez, H. D.; Morrissey, M. M. Discovery of novel non-peptide CCR1 receptor antagonists J. Med. Chem. 1999, 42, 4680-4694
96. Vallet, S.; Raje, N.; Ishitsuka, K.; Hideshima, T.; Podar, K.; Chhetri, S.; Pozzi, S.; Breitkreutz, I.; Kiziltepe, T.; Yasui, H.; Ocio, E. M.; Shiraishi, N.; Jin, J.; Okawa, Y.; Ikeda, H.; Mukherjee, S.; Vaghela, N.; Cirstea, D.; Ladetto, M.; Boccadoro, M.; Anderson, K. C. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts Blood 2007, 110, 3744-3752
97. Vergunst, C. E.; Gerlag, D. M.; von Moltke, L.; Karol, M.; Wyant, T.; Chi, X.; Matzkin, E.; Leach, T.; Tak, P. P. MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study Arthritis Rheum. 2009, 60, 3572-3581
98. Gladue, R. P.; Brown, M. F.; Zwillich, S. H. CCR1 antagonists: what have we learned from clinical trials Curr. Top. Med. Chem. 2010, 10, 1268-1277
99. Gladue, R. P.; Cole, S. H.; Roach, M. L.; Tylaska, L. A.; Nelson, R. T.; Shepard, R. M.; McNeish, J. D.; Ogborne, K. T.; Neote, K. S. The human specific CCR1 antagonist CP-481,715 inhibits cell infiltration and inflammatory responses in human CCR1 transgenic mice J. Immunol. 2006, 176, 3141-3148
100. Zhang, P.; Pennell, A. M. K.; Wright, J. J. K.; Wei, C.; Leleti, M. R.; Li, Y.; Li, L.; Xu, Y. Azaindazole Compounds and Methods of Use. US 7,524,845, 2009.
101. Dairaghi, D. J.; Zhang, P.; Wang, Y.; Seitz, L. C.; Johnson, D. A.; Miao, S.; Ertl, L. S.; Zeng, Y.; Powers, J. P.; Pennell, A. M.; Bekker, P.; Schall, T. J.; Jaen, J. C. Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose Clin. Pharmacol. Ther. 2011, 89, 726-734
102. Tak, P. P.; Balanescu, A.; Tseluyko, V.; Bojin, S.; Drescher, E.; Dairaghi, D.; Miao, S.; Marchesin, V.; Jaen, J.; Bekker, P.; Schall, T. J. Safety and Efficacy of Oral Chemokine Receptor 1 Antagonist CCX354-C in a Phase 2 Rheumatoid Arthritis Study. Presented at the 2011 American College of Rheumatology/Association of Reproductive Health Professionals (ACR/ARHP) Annual Meeting, Chicago, IL, 2011; https://acr.confex.com/acr/2011/webprogram/ Paper24548.html.
103. Merck's Research Pipeline and Selected Licensing Partners. Annual Report 2004. http://www.merck.com/finance/annualreport/ar2004/research-pipeline/.
104. Naya, A.; Ishikawa, M.; Matsuda, K.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Structure-activity relationships of xanthene carboxamides, novel CCR1 receptor antagonists Bioorg. Med. Chem. 2003, 11, 875-884
105. Kerstjens, H. A.; Bjermer, L.; Eriksson, L.; Dahlstrom, K.; Vestbo, J. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients Respir. Med. 2010, 104, 1297-1303
106. Butora, G.; Jiao, R.; Parsons, W. H.; Vicario, P. P.; Jin, H.; Ayala, J. M.; Cascieri, M. A.; Yang, L. 3-Amino-1-alkyl-cyclopentane carboxamides as small molecule antagonists of the human and murine CC chemokine receptor 2 Bioorg. Med. Chem. Lett. 2007, 17, 3636-3641
107. Butora, G.; Morriello, G. J.; Kothandaraman, S.; Guiadeen, D.; Pasternak, A.; Parsons, W. H.; Maccoss, M.; Vicario, P. P.; Cascieri, M. A.; Yang, L. 4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties Bioorg. Med. Chem. Lett. 2006, 16, 4715-4722
108. Yang, L.; Jiao, R. X.; Moyes, C.; Morriello, G.; Butora, G.; Shankaran, K.; Pasternak, A.; Goble, S. D.; Zhou, C.; MacCoss, M.; Cumiskey, A. M.; Peterson, L.; Forrest, M.; Ayala, J.; Jin, H.; DeMartino, J.; Mills, S. G. The Discovery of MK-0812, a Potent and Selective CCR2 Antagonist. Presented at the 233rd National Meeting of the American Chemical Society, Chicago, IL, Mar 25-29, 2007; www.acsmedchem.org/mediabstracts2007.pdf.
109. ClinicalTrials.gov. A Study To Assess the Effects of MK0812 on Disease Activity in Patients with Relapsing-Remitting Multiple Sclerosis As Measured by Magnetic Resonance Imaging (MRI). http://clinicaltrials.gov/ct2/show/record/ NCT00239655.
110. Abbadie, C.; Lindia, J. A.; Cumiskey, A. M.; Peterson, L. B.; Mudgett, J. S.; Bayne, E. K.; DeMartino, J. A.; MacIntyre, D. E.; Forrest, M. J. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2 Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 7947-7952
111. Abbadie, C.; Lindia, J. A.; Wang, H. CCR2 Antagonists for Treatment of Neuropathic Pain. US 20060205761, 2006.
112. Brodmerkel, C. M.; Huber, R.; Covington, M.; Diamond, S.; Hall, L.; Collins, R.; Leffet, L.; Gallagher, K.; Feldman, P.; Collier, P.; Stow, M.; Gu, X.; Baribaud, F.; Shin, N.; Thomas, B.; Burn, T.; Hollis, G.; Yeleswaram, S.; Solomon, K.; Friedman, S.; Wang, A.; Xue, C. B.; Newton, R. C.; Scherle, P.; Vaddi, K. Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344 J. Immunol. 2005, 175, 5370-5378
113. Xue, C.; Feng, H.; Cao, G.; Huang, T.; Glenn, J.; Anand, R.; Meloni, D.; Zhang, K.; Kong, L.; Wang, A.; Zhang, Y.; Zheng, C.; Xia, M.; Chen, L.; Tanaka, T.; Han, Q.; Robinson, D. J.; Modi, D.; Storace, L.; Shao, L.; Sharief, V.; Li, M.; Galya, L. G.; Covington, M.; Scherle, P.; Diamond, S.; Emm, T.; Yeleswaram, S.; Contel, N.; Vaddi, K.; Newton, R.; Hollis, G.; Friedman, S.; Metcalf, B. Discovery of INCB3284, a potent, selective, and orally bioavailable hCCR2 antagonist ACS Med. Chem. Lett. 2011, 2, 450-454
114. Hughes, R. O.; Rogier, D. J.; Devraj, R.; Zheng, C.; Cao, G.; Feng, H.; Xia, M.; Anand, R.; Xing, L.; Glenn, J.; Zhang, K.; Covington, M.; Morton, P. A.; Hutzler, J. M.; Davis, J. W., 2nd; Scherle, P.; Baribaud, F.; Bahinski, A.; Mo, Z. L.; Newton, R.; Metcalf, B.; Xue, C. B. Discovery of ((1 S,3 R)-1-isopropyl-3-((3 S,4 S)-3-methoxy-tetrahydro-2 H -pyran-4-ylamino)cyclopent yl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile Bioorg. Med. Chem. Lett. 2011, 21, 2626-2630
115. Trujillo, J. I.; Huang, W.; Hughes, R. O.; Rogier, D. J.; Turner, S. R.; Devraj, R.; Morton, P. A.; Xue, C. B.; Chao, G.; Covington, M. B.; Newton, R. C.; Metcalf, B. Design and synthesis of novel CCR2 antagonists: investigation of non-aryl/heteroaryl binding motifs Bioorg. Med. Chem. Lett. 2011, 21, 1827-1831
116. Zheng, C.; Cao, G.; Xia, M.; Feng, H.; Glenn, J.; Anand, R.; Zhang, K.; Huang, T.; Wang, A.; Kong, L.; Li, M.; Galya, L.; Hughes, R. O.; Devraj, R.; Morton, P. A.; Rogier, D. J.; Covington, M.; Baribaud, F.; Shin, N.; Scherle, P.; Diamond, S.; Yeleswaram, S.; Vaddi, K.; Newton, R.; Hollis, G.; Friedman, S.; Metcalf, B.; Xue, C. B. Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist Bioorg. Med. Chem. Lett. 2011, 21, 1442-1446
117. Incyte Announces First Quarter Financial Results and Provides Update on Drug Discovery and Development Programs. http://www.businesswire.com/portal/ site/google/index.jsp?ndmViewId=news-view&newsId=20060504005114& newsLang=en
118. Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study in Subjects with Osteoarthritic Pain of the Knee. http://clinicaltrials.gov/ct2/show/ NCT00689273?term=CCR2&rank=4.
119. Gilbert, J.; Lekstrom-Himes, J.; Donaldson, D.; Lee, Y.; Hu, M.; Xu, J.; Wyant, T.; Davidson, M. Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region Am. J. Cardiol. 2011, 107, 906-911
120. Sharrack, B.; Leach, T.; Jacobson, E.; Donaldson, D. D.; Xu, X.; Hu, M. Frequent MRI study of a novel CCR2 antagonist in relapsing-remitting multiple sclerosis Ann. Neurol. 2007, 62 (Suppl. 11) S74
121. Vergunst, C. E.; Gerlag, D. M.; Lopatinskaya, L.; Klareskog, L.; Smith, M. D.; van den Bosch, F.; Dinant, H. J.; Lee, Y.; Wyant, T.; Jacobson, E. W.; Baeten, D.; Tak, P. P. Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial Arthritis Rheum. 2008, 58, 1931-1939
122. Charvat, T. T.; Hu, C.; Jin, J.; Li, Y.; Melikian, A.; Pennell, A. M. K.; Punna, S.; Ungashe, S.; Zeng, Y. Triazolyl Pyridyl Benzenesulfonamides. US 20080039504, 2008.
123. Krasinski, A.; Punna, S.; Ungashe, S.; Wang, Q.; Zeng, Y. Fused Heteroaryl Pyridyl and Phenyl Benzenesulfonamides as CCR2 Modulators for the Treatment of Inflammation. US 7,884,110, 2011.
124. Chemocentryx/Inc. http://www.secinfo.com/d14D5a.t6zp.htm.
125. Sullivan, T. J.; Dairaghi, D. J.; Krasinski, A.; Miao, Z.; Wang, Y.; Zhao, B. N.; Baumgart, T.; Berahovich, R.; Ertl, L. S.; Pennell, A.; Seitz, L.; Miao, S.; Ungashe, S.; Wei, Z.; Johnson, D.; Boring, L.; Tsou, C. L.; Charo, I. F.; Bekker, P.; Schall, T. J.; Jaen, J. C. Characterization of CCX140-B, an orally bioavailable antagonist of the CCR2 chemokine receptor, for the treatment of type 2 diabetes and associated complications. J. Pharmacol. Exp. Ther. [Online early access]. DOI: 10.1124/jpet.111.190918. Published Online: Feb 29, 2012.
126. Hanefeld, M.; Schell, E.; Gouni-Berthold, I.; Melichar, M.; Vesela, I.; Sullivan, T.; Miao, S.; Johnson, D.; Jaen, J.; Bekker, P.; Schall, T. J. Oral chemokine receptor 2 antagonist CCX140-B shows safety and efficacy in type 2 diabetes mellitus Diabetes 2011, 60, A85
127. Carter, P. H.; Cherney, R. J.; Mangion, I. K. Advances in the discovery of CC chemokine receptor 2 antagonists Annu. Rep. Med. Chem. 2007, 42, 211-227
128. Carter, P. H.; Brown, G. D.; King, S. R.; Voss, M. E.; Tebben, A. J.; Cherney, R. J.; Mandlekar, S.; Lo, Y. C.; Yang, G.; Miller, P. B.; Scherle, P. A.; Zhao, Q.; Decicco, C. P. Discovery of an orally-bioavailable CC chemokine receptor 2 antagonist derived from an acyclic diaminoalcohol backbone Bioorg. Med. Chem. Lett. 2012, 22, 3311-3316
129. BMS-741672 for Diabetic Neuropathic Pain. http://clinicaltrials.gov/show/ NCT00683423.
130. Proof of Confidence Study of CCR2 Antagonist (BMS-741672) in Insulin Resistance. http://clinicaltrials.gov/ct2/show/NCT00699790?term=CCR2&rank=1
131. Lagu, B.; Gerchak, C.; Pan, M.; Hou, C.; Singer, M.; Malaviya, R.; Matheis, M.; Olini, G.; Cavender, D.; Wachter, M. Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma Bioorg. Med. Chem. Lett. 2007, 17, 4382-4386
132. Zhang, X.; Hufnagel, H.; Hou, C.; Opas, E.; McKenney, S.; Crysler, C.; O'Neill, J.; Johnson, D.; Sui, Z. Design, synthesis and SAR of indazole and benzoisoxazole containing 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists Bioorg. Med. Chem. Lett. 2011, 21, 6042-6048
133. Zhang, X.; Hufnagel, H.; Markotan, T.; Lanter, J.; Cai, C.; Hou, C.; Singer, M.; Opas, E.; McKenney, S.; Crysler, C.; Johnson, D.; Sui, Z. Overcoming hERG activity in the discovery of a series of 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists Bioorg. Med. Chem. Lett. 2011, 21, 5577-5582
134. Hou, C.; Singer, M.; Matheis, M.; JNJ-17166864, a Selective CCR2 Antagonist with Potential Therapeutic Implications for Inflammatory Diseases. Presented at the 104th International Conference American Thoracic Society, Toronto, Canada, 2008.
135. Varnes, J. G.; Gardner, D. S.; Santella, J. B., 3rd; Duncia, J. V.; Estrella, M.; Watson, P. S.; Clark, C. M.; Ko, S. S.; Welch, P.; Covington, M.; Stowell, N.; Wadman, E.; Davies, P.; Solomon, K.; Newton, R. C.; Trainor, G. L.; Decicco, C. P.; Wacker, D. A. Discovery of N -propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists Bioorg. Med. Chem. Lett. 2004, 14, 1645-1649
136. De Lucca, G. V.; Kim, U. T.; Vargo, B. J.; Duncia, J. V.; Santella, J. B., 3rd; Gardner, D. S.; Zheng, C.; Liauw, A.; Wang, Z.; Emmett, G.; Wacker, D.
137. Pruitt, J. R.; Batt, D. G.; Wacker, D. A.; Bostrom, L. L.; Booker, S. K.; McLaughlin, E.; Houghton, G. C.; Varnes, J. G.; Christ, D. D.; Covington, M.; Das, A. M.; Davies, P.; Graden, D.; Kariv, I.; Orlovsky, Y.; Stowell, N. C.; Vaddi, K. G.; Wadman, E. A.; Welch, P. K.; Yeleswaram, S.; Solomon, K. A.; Newton, R. C.; Decicco, C. P.; Carter, P. H.; Ko, S. S. CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity Bioorg. Med. Chem. Lett. 2007, 17, 2992-2997
138. Santella, J. B., 3rd; Gardner, D. S.; Yao, W.; Shi, C.; Reddy, P.; Tebben, A. J.; DeLucca, G. V.; Wacker, D. A.; Watson, P. S.; Welch, P. K.; Wadman, E. A.; Davies, P.; Solomon, K. A.; Graden, D. M.; Yeleswaram, S.; Mandlekar, S.; Kariv, I.; Decicco, C. P.; Ko, S. S.; Carter, P. H.; Duncia, J. V. From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis Bioorg. Med. Chem. Lett. 2008, 18, 576-585
139. Murdoch, R. D. Presented at the 4th James Black Conference, The Challenges of Drug Discovery and Development, University of Hertfordshire, U.K., Sep 3, 2006.
140. ClinicalTrials.gov. Oral GW766944 (Oral CCR3 Antagonist). http://clinicaltrials.gov/ct2/show/NCT01160224.
141. Greiff, L.; Ahlstrom-Emanuelsson, C.; Bahl, A.; Bengtsson, T.; Dahlstrom, K.; Erjefalt, J.; Widegren, H.; Andersson, M. Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis Respir. Res. 2010, 11, 1-9
142. Pascoe, S. J.; Bangert, C.; Bartlett, M.; Stary, G.; Stingl, G. QAP642, a CCR3 antagonist, attenuates eotaxin induced eosnlophil accumulation in the skin Am. J. Resp. Crit. Care Med. 2007, 175, A484 (abstracts issue)
143. Toda, M.; Nakamura, T.; Ohbayashi, M.; Ikeda, Y.; Dawson, M.; Aye, C. C.; Miyazaki, D.; Ono, S. J. Mechanisms of leukocyte trafficking in allergic diseases: insights into new therapies targeting chemokines and chemokine receptors Expert Rev. Clin. Immunol. 2007, 3, 351-364
144. Gauvreau, G. M.; Boulet, L. P.; Cockcroft, D. W.; Baatjes, A.; Cote, J.; Deschesnes, F.; Davis, B.; Strinich, T.; Howie, K.; Duong, M.; Watson, R. M.; Renzi, P. M.; O'Byrne, P. M. Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses Am. J. Respir. Crit. Care Med. 2008, 177, 952-958
145. Imaoka, H.; Campbell, H.; Babirad, I.; Watson, R. M.; Mistry, M.; Sehmi, R.; Gauvreau, G. M. TPI ASM8 reduces eosinophil progenitors in sputum after allergen challenge Clin. Exp. Allergy 2011, 41, 1740-1746
146. Ishida, T.; Iida, S.; Akatsuka, Y.; Ishii, T.; Miyazaki, M.; Komatsu, H.; Inagaki, H.; Okada, N.; Fujita, T.; Shitara, K.; Akinaga, S.; Takahashi, T.; Utsunomiya, A.; Ueda, R. The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma Clin. Cancer Res. 2004, 10, 7529-7539
147. Pease, J. E.; Horuk, R. Chemokine receptor antagonists:Part 1 Expert Opin. Ther. Pat. 2009, 19, 39-58
148. Yamamoto, K.; Utsunomiya, A.; Tobinai, K.; Tsukasaki, K.; Uike, N.; Uozumi, K.; Yamaguchi, K.; Yamada, Y.; Hanada, S.; Tamura, K.; Nakamura, S.; Inagaki, H.; Ohshima, K.; Kiyoi, H.; Ishida, T.; Matsushima, K.; Akinaga, S.; Ogura, M.; Tomonaga, M.; Ueda, R. Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma J. Clin. Oncol. 2010, 28, 1591-1598
149. Ishida, T.; Joh, T.; Uike, N.; Yamamoto, K.; Utsunomiya, A.; Yoshida, S.; Saburi, Y.; Miyamoto, T.; Takemoto, S.; Suzushima, H.; Tsukasaki, K.; Nosaka, K.; Fujiwara, H.; Ishitsuka, K.; Inagaki, H.; Ogura, M.; Akinaga, S.; Tomonaga, M.; Tobinai, K.; Ueda, R. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study J. Clin. Oncol. 2012, 30, 837-842
150. Procopiou, P. A.; Ford, A. J.; Graves, R. H.; Hall, D. A.; Hodgson, S. T.; Lacroix, Y. M.; Needham, D.; Slack, R. J. Lead optimisation of the N1 substituent of a novel series of indazole arylsulfonamides as CCR4 antagonists and identification of a candidate for clinical investigation Bioorg. Med. Chem. Lett. 2012, 22, 2730-2733
151. Intravenous Microdose Pharmacokinetic (PK) Study with [14C]-GSK2239633. http://clinicaltrials.gov/show/NCT01086462.
152. Moore, J. P.; Trkola, A.; Dragic, T. Co-receptors for HIV-1 entry Curr. Opin. Immunol. 1997, 9, 551-562
153. Wood, A.; Armour, D. The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS Prog. Med. Chem. 2005, 43, 239-271
154. Armour, D.; de Groot, M. J.; Edwards, M.; Perros, M.; Price, D. A.; Stammen, B. L.; Wood, A. The discovery of CCR5 receptor antagonists for the treatment of HIV infection: hit-to-lead studies ChemMedChem 2006, 1, 706-709
155. Dorr, P.; Westby, M.; Dobbs, S.; Griffin, P.; Irvine, B.; Macartney, M.; Mori, J.; Rickett, G.; Smith-Burchnell, C.; Napier, C.; Webster, R.; Armour, D.; Price, D.; Stammen, B.; Wood, A.; Perros, M. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity Antimicrob. Agents Chemother. 2005, 49, 4721-4732
156. Fatkenheuer, G.; Pozniak, A. L.; Johnson, M. A.; Plettenberg, A.; Staszewski, S.; Hoepelman, A. I.; Saag, M. S.; Goebel, F. D.; Rockstroh, J. K.; Dezube, B. J.; Jenkins, T. M.; Medhurst, C.; Sullivan, J. F.; Ridgway, C.; Abel, S.; James, I. T.; Youle, M.; van der Ryst, E. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1 Nat. Med. 2005, 11, 1170-1172
157. Lieberman-Blum, S. S.; Fung, H. B.; Bandres, J. C. Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection Clin. Ther. 2008, 30, 1228-1250
158. Palani, A.; Shapiro, S.; Clader, J. W.; Greenlee, W. J.; Cox, K.; Strizki, J.; Endres, M.; Baroudy, B. M. Discovery of 4-[(Z)-(4-bromophenyl)- (ethoxyimino)methyl]-1′-[(2,4- dimethyl-3- pyridinyl)carbonyl]-4′- methyl-1,4′- bipiperidine N -oxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection J. Med. Chem. 2001, 44, 3339-3342
159. McCombie, S. W.; Tagat, J. R.; Vice, S. F.; Lin, S. I.; Steensma, R.; Palani, A.; Neustadt, B. R.; Baroudy, B. M.; Strizki, J. M.; Endres, M.; Cox, K.; Dan, N.; Chou, C. C. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: Synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides Bioorg. Med. Chem. Lett. 2003, 13, 567-571
160. Este, J. A. SCH-351125 and SCH-350634. Schering-Plough Curr. Opin. Invest. Drugs 2002, 3, 379-383
161. Tagat, J. R.; McCombie, S. W.; Nazareno, D.; Labroli, M. A.; Xiao, Y.; Steensma, R. W.; Strizki, J. M.; Baroudy, B. M.; Cox, K.; Lachowicz, J.; Varty, G.; Watkins, R. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2-methoxy-1(R)-4- (trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist J. Med. Chem. 2004, 47, 2405-2408
162. Aidsmap. Second Company Halts CCR5 Inhibitor Study in Another Blow to New Drug Class. http://www.aidsmap.com/Second-company-halts-CCR5-inhibitor-study- in-another-blow-to-new-drug-class/page/1422234/.
163. Gulick, R. M.; Su, Z.; Flexner, C.; Hughes, M. D.; Skolnik, P. R.; Wilkin, T. J.; Gross, R.; Krambrink, A.; Coakley, E.; Greaves, W. L.; Zolopa, A.; Reichman, R.; Godfrey, C.; Hirsch, M.; Kuritzkes, D. R. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS clinical trials group 5211 J. Infect. Dis. 2007, 196, 304-312
164. AIDSMEDS. Merck Terminates Development of Its HIV Entry Inhibitor, Vicriviroc. http://www.aidsmeds.com/articles/hiv-vicriviroc-merck-1667-18742. shtml.
165. Maeda, K.; Nakata, H.; Koh, Y.; Miyakawa, T.; Ogata, H.; Takaoka, Y.; Shibayama, S.; Sagawa, K.; Fukushima, D.; Moravek, J.; Koyanagi, Y.; Mitsuya, H. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro J. Virol. 2004, 78, 8654-8662
166. Adkison, K. K.; Shachoy-Clark, A.; Fang, L.; Lou, Y.; O'Mara, K.; Berrey, M. M.; Piscitelli, S. C. Pharmacokinetics and short-term safety of 873140, a novel CCR5 antagonist, in healthy adult subjects Antimicrob. Agents Chemother. 2005, 49, 2802-2806
167. Nichols, W. G.; Steel, H. M.; Bonny, T.; Adkison, K.; Curtis, L.; Millard, J.; Kabeya, K.; Clumeck, N. Hepatotoxicity observed in clinical trials of aplaviroc (GW873140) Antimicrob. Agents Chemother. 2008, 52, 858-865
168. Moyle, G. The Last Word on Aplaviroc: A CCR5 Antagonist with Poor Efficacy. The Body; Remedy Health Media, LLC: New York, 2006; http://www.thebody.com/content/confs/hiv8/art39205.html.
169. Baba, M.; Nishimura, O.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Iizawa, Y.; Shiraishi, M.; Aramaki, Y.; Okonogi, K.; Ogawa, Y.; Meguro, K.; Fujino, M. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5698-5703
170. Shiraishi, M.; Aramaki, Y.; Seto, M.; Imoto, H.; Nishikawa, Y.; Kanzaki, N.; Okamoto, M.; Sawada, H.; Nishimura, O.; Baba, M.; Fujino, M. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety J. Med. Chem. 2000, 43, 2049-2063
171. Baba, M.; Takashima, K.; Miyake, H.; Kanzaki, N.; Teshima, K.; Wang, X.; Shiraishi, M.; Iizawa, Y. TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans Antimicrob. Agents Chemother. 2005, 49, 4584-4591
172. Seto, M.; Aramaki, Y.; Imoto, H.; Aikawa, K.; Oda, T.; Kanzaki, N.; Iizawa, Y.; Baba, M.; Shiraishi, M. Orally active CCR5 antagonists as anti-HIV-1 agents 2: synthesis and biological activities of anilide derivatives containing a pyridine N -oxide moiety Chem. Pharm. Bull. (Tokyo) 2004, 52, 818-829
173. Seto, M.; Aramaki, Y.; Okawa, T.; Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.; Iizawa, Y.; Baba, M.; Shiraishi, M. Orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety Chem. Pharm. Bull. (Tokyo) 2004, 52, 577-590
174. Takeda To License CCR5 Antagonists for Treatment of HIV Infection to Tobira Therapeutics, Inc. http://www.takeda.com/press/article-27377.html.
175. Lalezari, J.; Gathe, J.; Brinson, C.; Thompson, M.; Cohen, C.; Dejesus, E.; Galindez, J.; Ernst, J. A.; Martin, D. E.; Palleja, S. M. Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects J. Acquired Immune Defic. Syndr. 2011, 57, 118-125
176. Xue, C.-B.; Chen, L.; Cao, G.; Zhang, K.; Wang, A.; Meloni, D.; Glenn, J.; Anand, R.; Xia, M.; Kong, L.; Huang, T.; Feng, H.; Zheng, C.; Li, M.; Galya, L.; Zhou, J.; Shin, N.; Baribaud, F.; Solomon, K.; Scherle, P.; Zhao, B.; Diamond, S.; Emm, T.; Keller, D.; Contel, N.; Yeleswaram, S.; Vaddi, K.; Hollis, G.; Newton, R.; Friedman, S.; Metcalf, B. Discovery of INCB9471, a potent, selective, and orally bioavailable CCR5 antagonist with potent anti-HIV-1 activity ACS Med. Chem. Lett. 2010, 1, 483-487
177. Shin, N.; Solomon, K.; Zhou, N.; Wang, K. H.; Garlapati, V.; Thomas, B.; Li, Y.; Covington, M.; Baribaud, F.; Erickson-Viitanen, S.; Czerniak, P.; Contel, N.; Liu, P.; Burn, T.; Hollis, G.; Yeleswaram, S.; Vaddi, K.; Xue, C. B.; Metcalf, B.; Friedman, S.; Scherle, P.; Newton, R. Identification and characterization of INCB9471, an allosteric noncompetitive small-molecule antagonist of C-C chemokine receptor 5 with potent inhibitory activity against monocyte migration and HIV-1 infection J. Pharmacol. Exp. Ther. 2011, 338, 228-239
178. Cohen, C.; DeJesus, E.; Mills, A.; Pierone, G.; Kumar, P.; Ruane, P.; Elion, R.; Fusco, G.; Levy, R.; Solomon, K. Potent Antiretroviral Activity of the Once Daily Antagonist INCB009471 over 14 Days of Monotherapy. Presented at the 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, 2007.
179. Dalton, P. Incyte Halts Development of Promising New CCR5 Drug. The Body; Remedy Health Media, LLC: New York; http://www.thebody.com/content/art46326. html.
180. Burrows, J. N.; Cumming, J. G.; Fillery, S. M.; Hamlin, G. A.; Hudson, J. A.; Jackson, R. J.; McLaughlin, S.; Shaw, J. S. Modulators of the human CCR5 receptor. Part 1: Discovery and initial SAR of 1-(3,3-diphenylpropyl)- piperidinyl amides and ureas Bioorg. Med. Chem. Lett. 2005, 15, 25-28
181. Cumming, J. G.; Cooper, A. E.; Grime, K.; Logan, C. J.; McLaughlin, S.; Oldfield, J.; Shaw, J. S.; Tucker, H.; Winter, J.; Whittaker, D. Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3,3-diphenylpropyl)- piperidinyl phenylacetamides Bioorg. Med. Chem. Lett. 2005, 15, 5012-5015
182. Cumming, J. G.; Brown, S. J.; Cooper, A. E.; Faull, A. W.; Flynn, A. P.; Grime, K.; Oldfield, J.; Shaw, J. S.; Shepherd, E.; Tucker, H.; Whittaker, D. Modulators of the human CCR5 receptor. Part 3: SAR of substituted 1-[3-(4-methanesulfonylphenyl)-3-phenylpropyl]-piperidinyl phenylacetamides Bioorg. Med. Chem. Lett. 2006, 16, 3533-3536
183. Cumming, J. G.; Tucker, H.; Oldfield, J.; Fielding, C.; Highton, A.; Faull, A.; Wild, M.; Brown, D.; Wells, S.; Shaw, J. Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis Bioorg. Med. Chem. Lett. 2012, 22, 1655-1659
184. Gerlag, D. M.; Hollis, S.; Layton, M.; Vencovsky, J.; Szekanecz, Z.; Braddock, M.; Tak, P. P. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate Arthritis Rheum. 2010, 62, 3154-3160
185. Jacobson, J.; Thompson, M.; Fischl, M. Phase 2a Study of PRO 140 in HIV-Infected Adults. Presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2009), San Francisco, CA 2009; Abstract H-1229.
186. Lalezari, J.; Yadavalli, G. K.; Para, M.; Richmond, G.; Dejesus, E.; Brown, S. J.; Cai, W.; Chen, C.; Zhong, J.; Novello, L. A.; Lederman, M. M.; Subramanian, G. M. Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients J. Infect. Dis. 2008, 197, 721-727
187. Miltz, W. Dual CCR2/ CCR5Antagonists: A New Approach for the Treatment of Autoimmune Diseases. Presented at the 235th National Meeting of the American Chemical Society, New Orleans, LA, Apr 6-10, 2008; http://oasys2.confex.com/acs/ 235nm/techprogram/S26267.HTM.
188. Urnov, F. D.; Rebar, E. J.; Holmes, M. C.; Zhang, H. S.; Gregory, P. D. Genome editing with engineered zinc finger nucleases Nat. Rev. Genet. 2010, 11, 636-646
189. Liu, R.; Paxton, W. A.; Choe, S.; Ceradini, D.; Martin, S. R.; Horuk, R.; MacDonald, M. E.; Stuhlmann, H.; Koup, R. A.; Landau, N. R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection Cell 1996, 86, 367-377
190. Saruta, M.; Yu, Q. T.; Avanesyan, A.; Fleshner, P. R.; Targan, S. R.; Papadakis, K. A. Phenotype and effector function of CC chemokine receptor 9-expressing lymphocytes in small intestinal Crohn's disease J. Immunol. 2007, 178, 3293-3300
191. Ungashe, S.; Wright, J. J.; Pennell, A. Aryl Sulfonamides. US 7,932,252, 2011.
192. Vercirnon. http://www.chemspider.com/Chemical-Structure.8518913.html.
193. Walters, M. J.; Wang, Y.; Lai, N.; Baumgart, T.; Zhao, B. N.; Dairaghi, D. J.; Bekker, P.; Ertl, L. S.; Penfold, M. E.; Jaen, J. C.; Keshav, S.; Wendt, E.; Pennell, A.; Ungashe, S.; Wei, Z.; Wright, J. J.; Schall, T. J. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease J. Pharmacol. Exp. Ther. 2010, 335, 61-69
194. Keshav, S. CCX282-B, an Orally Active Inhibitor of Chemokine Receptor CCR9, in a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study in Moderate to Severe Crohn's Disease. Presented at the 14th United European Gastroenterology Week (UEGW 2006), Berlin, 2006.
195. White, J. R.; Lee, J. M.; Young, P. R.; Hertzberg, R. P.; Jurewicz, A. J.; Chaikin, M. A.; Widdowson, K.; Foley, J. J.; Martin, L. D.; Griswold, D. E.; Sarau, H. M. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration J. Biol. Chem. 1998, 273, 10095-10098
196. Widdowson, K. L.; Elliott, J. D.; Veber, D. F.; Nie, H.; Rutledge, M. C.; McCleland, B. W.; Xiang, J. N.; Jurewicz, A. J.; Hertzberg, R. P.; Foley, J. J.; Griswold, D. E.; Martin, L.; Lee, J. M.; White, J. R.; Sarau, H. M. Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor J. Med. Chem. 2004, 47, 1319-1321
197. Jin, Q.; Nie, H.; McCleland, B. W.; Widdowson, K. L.; Palovich, M. R.; Elliott, J. D.; Goodman, R. M.; Burman, M.; Sarau, H. M.; Ward, K. W.; Nord, M.; Orr, B. M.; Gorycki, P. D.; Busch-Petersen, J. Discovery of potent and orally bioavailable N, N ′-diarylurea antagonists for the CXCR2 chemokine receptor Bioorg. Med. Chem. Lett. 2004, 14, 4375-4378
198. Lazaar, A. L.; Sweeney, L. E.; MacDonald, A. J.; Alexis, N. E.; Chen, C.; Tal-Singer, R. SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans Br. J. Clin. Pharmacol. 2011, 72, 282-293
199. Allegretti, M.; Bertini, R.; Cesta, M. C.; Bizzarri, C.; Di Bitondo, R.; Di Cioccio, V.; Galliera, E.; Berdini, V.; Topai, A.; Zampella, G.; Russo, V.; Di Bello, N.; Nano, G.; Nicolini, L.; Locati, M.; Fantucci, P.; Florio, S.; Colotta, F. 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors J. Med. Chem. 2005, 48, 4312-4331
200. Ginestier, C.; Liu, S.; Diebel, M. E.; Korkaya, H.; Luo, M.; Brown, M.; Wicinski, J.; Cabaud, O.; Charafe-Jauffret, E.; Birnbaum, D.; Guan, J. L.; Dontu, G.; Wicha, M. S. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts J. Clin. Invest. 2010, 120, 485-497
201. Suling, L.; Korkaya, H.; Wicha, M. S. Are Cancer Stem Cells Ready for Prime Time? The Scientist; LabX Media Group: New York; http://the-scientist.com/ 2012/04/01/are-cancer-stem-cells-ready-for-prime-time/.
202. Dwyer, M. P.; Yu, Y.; Chao, J.; Aki, C.; Biju, P.; Girijavallabhan, V.; Rindgen, D.; Bond, R.; Mayer-Ezel, R.; Jakway, J.; Hipkin, R. W.; Fossetta, J.; Gonsiorek, W.; Bian, H.; Fan, X.; Terminelli, C.; Fine, J.; Lundell, D.; Merritt, J. R.; Rokosz, L. L.; Kaiser, B.; Li, G.; Wang, W.; Stauffer, T.; Ozgur, L.; Baldwin, J.; Taveras, A. G. Discovery of 2-hydroxy- N, N -dimethyl-3-{2-[[(R)-1-(5- methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobut-1- enylamino}benzamide (SCH 527123): a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist J. Med. Chem. 2006, 49, 7603-7606
203. Gonsiorek, W.; Fan, X.; Hesk, D.; Fossetta, J.; Qiu, H.; Jakway, J.; Billah, M.; Dwyer, M.; Chao, J.; Deno, G.; Taveras, A.; Lundell, D. J.; Hipkin, R. W. Pharmacological characterization of Sch527123, a potent allosteric CXCR1/CXCR2 antagonist J. Pharmacol. Exp. Ther. 2007, 322, 477-485
204. Chapman, R. W.; Minnicozzi, M.; Celly, C. S.; Phillips, J. E.; Kung, T. T.; Hipkin, R. W.; Fan, X.; Rindgen, D.; Deno, G.; Bond, R.; Gonsiorek, W.; Billah, M. M.; Fine, J. S.; Hey, J. A. A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation J. Pharmacol. Exp. Ther. 2007, 322, 486-493
205. Holz, O.; Khalilieh, S.; Ludwig-Sengpiel, A.; Watz, H.; Stryszak, P.; Soni, P.; Tsai, M.; Sadeh, J.; Magnussen, H. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects Eur. Respir. J. 2010, 35, 564-570
206. Jenh, C. H.; Cox, M. A.; Cui, L.; Reich, E. P.; Sullivan, L.; Chen, S. C.; Kinsley, D.; Qian, S.; Kim, S. H.; Rosenblum, S.; Kozlowski, J.; Fine, J. S.; Zavodny, P. J.; Lundell, D. A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection BMC Immunol. 2012, 13, 13-22
207. Johnson, M.; Li, A. R.; 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
208. Tonn, G. R.; Wong, S. G.; Wong, S. C.; Johnson, M. G.; Ma, J.; Cho, R.; Floren, L. C.; Kersey, K.; Berry, K.; Marcus, A. P.; Wang, X.; Van Lengerich, B.; Medina, J. C.; Pearson, P. G.; Wong, B. K. An inhibitory metabolite leads to dose- and time-dependent pharmacokinetics of (R)- N -{1-[3-(4-ethoxy-phenyl)-4- oxo-3,4-dihydro-pyrido[2,3- d ]pyrimidin-2-yl]-ethy l}- N -pyridin-3-yl-methyl- 2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in human subjects after multiple dosing Drug Metab. Dispos. 2009, 37, 502-513
209. Peled, A.; Grabovsky, V.; Habler, L.; Sandbank, J.; Arenzana-Seisdedos, F.; Petit, I.; Ben-Hur, H.; Lapidot, T.; Alon, R. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow J. Clin. Invest. 1999, 104, 1199-1211
210. Broxmeyer, H. E.; Orschell, C. M.; Clapp, D. W.; Hangoc, G.; Cooper, S.; Plett, P. A.; Liles, W. C.; Li, X.; Graham-Evans, B.; Campbell, T. B.; Calandra, G.; Bridger, G.; Dale, D. C.; Srour, E. F. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist J. Exp. Med. 2005, 201, 1307-1318
211. DiPersio, J. F.; Micallef, I. N.; Stiff, P. J.; Bolwell, B. J.; Maziarz, R. T.; Jacobsen, E.; Nademanee, A.; McCarty, J.; Bridger, G.; Calandra, G. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma J. Clin. Oncol. 2009, 27, 4767-4773
212. Shia, K. S.; Hakimelahi, G. H.; Zhu, J. L.; Yen, C. F.; Huang, Y. H.; Xiang, Y.; Chen, H. C.; Changhua, C. W. Polyamine Compounds for Treating Chemokine Receptor Mediated Diseases. US 7,399,776, 2008.
213. Chung, D. T.; Chang, L.; Huang, Y.; Tsai, C.; Hsu, C.; King, C. R.; Yuan, J. H.; Yen, C.; Chen, Y.; Lu, Y. C.; Hsu, M. TG-0054, a Novel and Potent Stem Cell Mobilizer, Displays Excellent PK/PD and Safety Profile in Phase I Trial. Presented at the 51st ASH Meeting, New Orleans, LA, 2009.
214. Zumbrunn, J.; Demarco, S. J.; Lociuro, S.; Vrijbloed, J. W.; Gombert, F.; Mukherjee, R.; Moehle, K.; Obrecht, D.; Robinson, J. A.; Henze, H.; Romagnoli, B.; Ludin, C. Template Fixed 8 Hairpin Peptidomimetics with CXCR4 Antagonizing Activity. US 7,786,078, 2010.
215. Roccaro, A. M.; Sacco, A.; Kuhne, M.; Azab, A. K.; Maiso, P.; Zhang, Y.; Liu, Y.; Azab, F.; Issa, G. C.; Quang, P.; Ngo, H. T.; Pan, C.; Choen, L.; Cardarelli, P. M.; Ghobrial, I. M. The New CXCR4 Inhibitor MDX-1338 Exerts Anti-Tumor Activity in Multiple Myeloma. Presented at 53rd ASH Meeting, San Diego CA, 2011; Abstract 1844.
216. Fujii, N.; Tamamura, H.; Hori, A. CXCR4 Antagonist and Use Thereof. US 8,017,585, 2011.
217. Proudfoot, A. E. Is CCR2 the right chemokine receptor to target in rheumatoid arthritis? Arthritis Rheum. 2008, 58, 1889-1891
218. Karpus, W. J.; Lukacs, N. W.; McRae, B. L.; Strieter, R. M.; Kunkel, S. L.; Miller, S. D. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis J. Immunol. 1995, 155, 5003-5010
219. Liang, M.; Mallari, C.; Rosser, M.; Ng, H. P.; May, K.; Monahan, S.; Bauman, J. G.; Islam, I.; Ghannam, A.; Buckman, B.; Shaw, K.; Wei, G. P.; Xu, W.; Zhao, Z.; Ho, E.; Shen, J.; Oanh, H.; Subramanyam, B.; Vergona, R.; Taub, D.; Dunning, L.; Harvey, S.; Snider, R. M.; Hesselgesser, J.; Morrissey, M. M.; Perez, H. D. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1 J. Biol. Chem. 2000, 275, 19000-19008
220. Aktas, O.; Kury, P.; Kieseier, B.; Hartung, H. P. Fingolimod is a potential novel therapy for multiple sclerosis Nat. Rev. Neurol. 2010, 6, 373-382
221. Fleishaker, D. L.; Garcia Meijide, J. A.; Petrov, A.; Kohen, M. D.; Wang, X.; Menon, S.; Stock, T. C.; Mebus, C. A.; Goodrich, J. M.; Mayer, H. B.; Zeiher, B. G. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial Arthritis Res. Ther. 2012, 14, R11
222. Plater-Zyberk, C.; Hoogewerf, A. J.; Proudfoot, A. E.; Power, C. A.; Wells, T. N. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice Immunol. Lett. 1997, 57, 117-120
223. Vierboom, M. P.; Zavodny, P. J.; Chou, C. C.; Tagat, J. R.; Pugliese-Sivo, C.; Strizki, J.; Steensma, R. W.; McCombie, S. W.; Celebi-Paul, L.; Remarque, E.; Jonker, M.; Narula, S. K.; Hart, B. Inhibition of the development of collagen-induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5 Arthritis Rheum. 2005, 52, 627-636
224. Yang, Y. F.; Mukai, T.; Gao, P.; Yamaguchi, N.; Ono, S.; Iwaki, H.; Obika, S.; Imanishi, T.; Tsujimura, T.; Hamaoka, T.; Fujiwara, H. A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses Eur. J. Immunol. 2002, 32, 2124-2132
225. Pokorny, V.; McQueen, F.; Yeoman, S.; Merriman, M.; Merriman, T.; Harrison, A.; Highton, J.; McLean, L. Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis Ann. Rheum. Dis. 2004, 64, 4897-490
226. Bruhl, H.; Cihak, J.; Schneider, M. A.; Plachy, J.; Rupp, T.; Wenzel, I.; Shakarami, M.; Milz, S.; Ellwart, J. W.; Stangassinger, M.; Schlondorff, D.; Mack, M. Dual role of CCR2 during initiation and progression of collagen-induced arthritis: evidence for regulatory activity of CCR2+ T cells J. Immunol. 2004, 172, 890-898
227. Lebre, M. C.; Vergunst, C. E.; Choi, I. Y.; Aarrass, S.; Oliveira, A. S.; Wyant, T.; Horuk, R.; Reedquist, K. A.; Tak, P. P. Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis PLoS One 2011, 6, e21772
228. Flier, J.; Boorsma, D. M.; van Beek, P. J.; Nieboer, C.; Stoof, T. J.; Willemze, R.; Tensen, C. P. Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation J. Pathol. 2001, 194, 398-405
229. Xie, J. H.; Nomura, N.; Lu, M.; Chen, S. L.; Koch, G. E.; Weng, Y.; Rosa, R.; Di Salvo, J.; Mudgett, J.; Peterson, L. B.; Wicker, L. S.; DeMartino, J. A. Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation J. Leukocyte Biol. 2003, 73, 771-780
230. Hancock, W. W.; Lu, B.; Gao, W.; Csizmadia, V.; Faia, K.; King, J. A.; Smiley, S. T.; Ling, M.; Gerard, N. P.; Gerard, C. Requirement of the chemokine receptor CXCR3 for acute allograft rejection J. Exp. Med. 2000, 192, 1515-1520
231. Clark, R. A.; Kupper, T. S. Misbehaving macrophages in the pathogenesis of psoriasis J. Clin. Invest. 2006, 116, 2084-2087
232. Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands Drug Discovery Today 2004, 9, 641-651
233. Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm J. Med. Chem. 2005, 48, 6523-6543
234. Bymaster, F. P.; Calligaro, D. O.; Falcone, J. F.; Marsh, R. D.; Moore, N. A.; Tye, N. C.; Seeman, P.; Wong, D. T. Radioreceptor binding profile of the atypical antipsychotic olanzapine Neuropsychopharmacology 1996, 14, 87-96
235. Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Structure-activity relationships of 2-(benzothiazolylthio) acetamide class of CCR3 selective antagonist Chem. Pharm. Bull. (Tokyo) 2003, 51, 697-701
236. Sabroe, I.; Peck, M. J.; Van Keulen, B. J.; Jorritsma, A.; Simmons, G.; Clapham, P. R.; Williams, T. J.; Pease, J. E. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry J. Biol. Chem. 2000, 275, 25985-25992
237. Naya, A.; Kobayashi, K.; Ishikawa, M.; Ohwaki, K.; Saeki, T.; Noguchi, K.; Ohtake, N. Discovery of a novel CCR3 selective antagonist Bioorg. Med. Chem. Lett. 2001, 11, 1219-1223
238. Seto, M.; Aikawa, K.; Miyamoto, N.; Aramaki, Y.; Kanzaki, N.; Takashima, K.; Kuze, Y.; Iizawa, Y.; Baba, M.; Shiraishi, M. Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety J. Med. Chem. 2006, 49, 2037-2048
239. Hersperger, R.; Janser, P.; Pfenninger, E.; Wuethrich, H. J.; Miltz, W. Chemokine Receptor Antagonists. US 20070155721, 2007.
240. Cole, P.; Vasiliou, S. Highlights from the 50th interscience conference on anti-microbial agents and chemotherapy (ICAAC) Drugs Future 2010, 35, 1045-1067
241. Walters, I.; Austin, C.; Austin, R.; Bonnert, R.; Cage, P.; Christie, M.; Ebden, M.; Gardiner, S.; Grahames, C.; Hill, S.; Hunt, F.; Jewell, R.; Lewis, S.; Martin, I.; David, N.; David, R. Evaluation of a series of bicyclic CXCR2 antagonists Bioorg. Med. Chem. Lett. 2008, 18, 798-803
242. Suzuki, K.; Morokata, T.; Morihira, K.; Sato, I.; Takizawa, S.; Kaneko, M.; Takahashi, K.; Shimizu, Y. A dual antagonist for chemokine CCR3 receptor and histamine H1 receptor Eur. J. Pharmacol. 2007, 563, 224-232
243. Melancon, B. J.; Hopkins, C. R.; Wood, M. R.; Emmitte, K. A.; Niswender, C. M.; Christopoulos, A.; Conn, P. J.; Lindsley, C. W. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery J. Med. Chem. 2012, 55, 1445-1464
244. Schnickel, G. T.; Bastani, S.; Hsieh, G. R.; Shefizadeh, A.; Bhatia, R.; Fishbein, M. C.; Belperio, J.; Ardehali, A. Combined CXCR3/CCR5 blockade attenuates acute and chronic rejection J. Immunol. 2008, 180, 4714-4721
245. Gao, W.; Faia, K. L.; Csizmadia, V.; Smiley, S. T.; Soler, D.; King, J. A.; Danoff, T. M.; Hancock, W. W. Beneficial effects of targeting CCR5 in allograft recipients Transplantation 2001, 72, 1199-1205
246. Li, L.; Huang, L.; Sung, S. S.; Vergis, A. L.; Rosin, D. L.; Rose, C. E., Jr.; Lobo, P. I.; Okusa, M. D. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury Kidney Int. 2008, 74, 1526-1537
247. Jerath, M. R.; Liu, P.; Struthers, M.; Demartino, J. A.; Peng, R.; Peterson, L. B.; Cumiskey, A. M.; Yang, L.; Rojas, M.; Patel, D. D.; Fong, A. M. Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation Thromb. J. 2010, 8, 14
248. BusinessWire. Ligand Licenses DARA Program to Retrophin. http://www.businesswire.com/news/home/20120221005513/en/Ligand-Licenses-DARA- Program-Retrophin.
249. Ohshima, E.; Takami, H.; Harakawa, H.; Sato, H.; Obase, H.; Miki, I.; Ishii, A.; Ishii, H.; Sasaki, Y.; Ohmori, K.; Karasawa, A.; Kubo, K. Dibenz[ b, e ]oxepin derivatives: novel antiallergic agents possessing thromboxane A2 and histamine H1 dual antagonizing activity J. Med. Chem. 1993, 36, 417-420
250. Schall, T. J.; Proudfoot, A. E. Overcoming hurdles in developing successful drugs targeting chemokine receptors Nat. Rev. Immunol. 2011, 11, 355-363
251. O'Boyle, G.; Fox, C. R.; Walden, H. R.; Willet, J. D.; Mavin, E. R.; Hine, D. W.; Palmer, J. M.; Barker, C. E.; Lamb, C. A.; Ali, S.; Kirby, J. A. Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 4598-4603
252. Takeda, A.; Baffi, J. Z.; Kleinman, M. E.; Cho, W. G.; Nozaki, M.; Yamada, K.; Kaneko, H.; Albuquerque, R. J.; Dridi, S.; Saito, K.; Raisler, B. J.; Budd, S. J.; Geisen, P.; Munitz, A.; Ambati, B. K.; Green, M. G.; Ishibashi, T.; Wright, J. D.; Humbles, A. A.; Gerard, C. J.; Ogura, Y.; Pan, Y.; Smith, J. R.; Grisanti, S.; Hartnett, M. E.; Rothenberg, M. E.; Ambati, J. CCR3 is a target for age-related macular degeneration diagnosis and therapy Nature 2009, 460, 225-230
253. Villeda, S. A.; Luo, J.; Mosher, K. I.; Zou, B.; Britschgi, M.; Bieri, G.; Stan, T. M.; Fainberg, N.; Ding, Z.; Eggel, A.; Lucin, K. M.; Czirr, E.; Park, J. S.; Couillard-Despres, S.; Aigner, L.; Li, G.; Peskind, E. R.; Kaye, J. A.; Quinn, J. F.; Galasko, D. R.; Xie, X. S.; Rando, T. A.; Wyss-Coray, T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function Nature 2011, 477, 90-94
254. Shimaoka, T.; Nakayama, T.; Fukumoto, N.; Kume, N.; Takahashi, S.; Yamaguchi, J.; Minami, M.; Hayashida, K.; Kita, T.; Ohsumi, J.; Yoshie, O.; Yonehara, S. Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells J. Leukocyte Biol. 2004, 75, 267-274
255. Sheikine, Y.; Sirsjo, A. CXCL16/SR-PSOX - a friend or a foe in atherosclerosis? Atherosclerosis 2008, 197, 487-495
256. Terashima, Y.; Onai, N.; Murai, M.; Enomoto, M.; Poonpiriya, V.; Hamada, T.; Motomura, K.; Suwa, M.; Ezaki, T.; Haga, T.; Kanegasaki, S.; Matsushima, K. Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis Nat. Immunol. 2005, 6, 827-835
257. Toda, E.; Terashima, Y.; Sato, T.; Hirose, K.; Kanegasaki, S.; Matsushima, K. FROUNT is a common regulator of CCR2 and CCR5 signaling to control directional migration J. Immunol. 2009, 183, 6387-6394