Therapeutic potential of CCR1 antagonists for multiple myeloma

Future Medicinal Chemistry

Volumn 3, Issue 15, 2011, Pages 1889-1908

  Karash, Angela R ^a   Gilchrist, Annette ^a  

^a MIDWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [5 CHLORO 2 [2 [4 (4 FLUOROBENZYL) 2 METHYL 1 PIPERAZINYL] 2 OXOETHOXY]PHENYL]UREA; A4B7; AZD 4818; BMS 817399; BX 513; C 4462; C 6448; CCX 105; CCX 354; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR1; CHEMOKINE RECEPTOR CCR1 ANTAGONIST; CP 481715; LIGAND; METHOTREXATE; MLN 3701; MLN 3897; UNCLASSIFIED DRUG;

CHRONIC OBSTRUCTIVE LUNG DISEASE; DEEP VEIN THROMBOSIS; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG INDUSTRY; DRUG POTENCY; DRUG TOLERABILITY; HUMAN; MULTIPLE MYELOMA; MULTIPLE SCLEROSIS; NONHUMAN; PELVIS PAIN SYNDROME; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SKIN ALLERGY; STRUCTURE ACTIVITY RELATION; TREATMENT RESPONSE; UNSPECIFIED SIDE EFFECT;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; MULTIPLE MYELOMA; RECEPTORS, CCR1; SIGNAL TRANSDUCTION;

EID: 80054927712     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.11.144     Document Type: Review

References (130)

1. Neote K, DiGregorio D, Mak J, Horuk R, Schall T. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell 72, 415-425. (1993).
2. Gao J, Kuhns D, Tiffany H et al. Structure and functional expression of the human macrophage inflammatory protein 1 α/RANTES receptor. J. Exp. Med. 177, 1421-1427 (1993).
3. Gao J, Murphy P. Cloning and differential tissue-specific expression of three mouse beta chemokine receptor-like genes, including the gene for a functional macrophage inflammatory protein-1 αreceptor. J. Biol. Chem. 270, 17494-17501 (1995).
4. Bonecchi R, Polentarutti N, Luini W et al. Up-regulation of CCR1 and CCR3 and induction of chemotaxis to CC chemokines by IFN-gamma in human neutrophils. J. Immunol. 162, 474-479 (1999).
5. Sallusto F, Schaerli P, Loetscher P et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28, 2760-2769 (1998).
6. Loetscher P, Seitz M, Baggiolini M, Moser B. Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. J. Exp. Med. 184, 569-577 (1996).
7. Uguccioni M, Mackay C, Ochensberger B et al. High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines. J. Clin. Invest. 100, 1137-1143. (1997).
8. Sabroe I, Hartnell A, Jopling L et al. Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. J. Immunol. 162, 2946-2955 (1999).
9. Cheng S, Lai J, Lukacs N, Kunkel S. Granulocyte-macrophage colony stimulating factor up-regulates CCR1 in human neutrophils. J. Immunol. 166, 1178-1184 (2001).
10. Inngjerdingen M, Damaj B, Maghazachi A. Expression and regulation of chemokine receptors in human natural killer cells. Blood 97, 367-375 (2001).
11. Juremalm M, Olsson N, Nilsson G. Selective CCL5/RANTES-induced mast cell migration through interactions with chemokine receptors CCR1 and CCR4. Biochem. Biophys. Res. Commun. 297, 480-485. (2002).
12. Lean J, Murphy C, Fuller K, Chambers T. CCL9/MIP-1gamma and its receptor CCR1 are the major chemokine ligand/receptor species expressed by osteoclasts. J. Cell. Biochem. 87, 386-393 (2002).
13. Gerard C, Frossard J, Bhatia M et al. Targeted disruption of the β-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J. Clin. Invest. 100, 2022-2027 (1997).
14. Furuichi K, Gao J, Horuk R, Wada T, Kaneko S, Murphy P. Chemokine receptor CCR1 regulates inflammatory cell infiltration after renal ischemia-reperfusion injury. J. Immunol. 181, 8670-8676. (2008).
15. Liehn E, Merx M, Postea O et al. Ccr1 deficiency reduces inflammatory remodelling and preserves left ventricular function after myocardial infarction. J. Cell. Mol. Med. 12, 496-506 (2008).
16. Graham G, Nibbs R. Chemokine receptors: a structural overview. In: The Chemokine Receptors. Harrison, J, Lukacs, N (Eds.) Humana Press, Totowa, NJ, USA, 31-54. (2007)
17. Charo I, Ransohoff R. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610-621 (2006).
18. Hoshino A, Iimura T, Ueha S et al. Deficiency of chemokine receptor CCR1 causes osteopenia due to impaired functions of osteoclasts and osteoblasts. J. Biol. Chem. 285, 28826-28837 (2010). This paper established that CCR1-deficient mice exhibit osteopenia and demonstrated that lack of CCR1 affects not only osteoclastogenesis but the differentiation and function of osteoblasts as well.
19. Tsubaki M, Kato C, Isono A et al. Macrophage inflammatory protein-1a induces osteoclast formation by activation of the MEK/ERK/c-Fos pathway and inhibition of the p38MAPK/IRF-3/IFN-βpathway. J. Cell. Biochem. 111, 1661-1672 (2010).
20. Abe M, Hiura K, Wilde J et al. Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma. Blood 100, 2195-2202 (2002).
21. Votta B, White J, Dodds R et al. CKβ-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues. J. Cell. Physiol. 183, 196-207 (2000).
22. Cappellen D, Luong-Nguyen N, Bongiovanni S, Grenet O, Wanke C, Susa M. Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for the receptor activator of NFkappa B. J. Biol. Chem. 277, 21971-21982 (2002).
23. Cho K, Joo S, Han H, Ryu K, Woo S. Osteoclast activation by receptor activator of NF-kappaB ligand enhances the mobilization of hematopoietic progenitor cells from the bone marrow in acute injury. Int. J. Mol. Med. 26, 557-563 (2010).
24. Yu X, Huang Y, Collin-Osdoby P, Osdoby P. CCR1 chemokines promote the chemotactic recruitment, RANKL development, and motility of osteoclasts and are induced by inflammatory cytokines in osteoblasts. J. Bone. Miner. Res. 19, 2065-2077 (2004). Assessment of CCR1 mRNA expression indicated the receptor was not only expressed in murine marrow cells, it was the most prominent CCR in RAW cells. Moreover, expression of CCR1 in these cells was upregulated by RANKL. While CCL3 and CCL5 stimulated chemotaxis of marrow or RAW cell precursors, they did not alter OC resorption activity, adhesion or survival.
25. Kukita T, Nakao J, Hamada F et al. Recombinant LD78 protein, a member of the small cytokine family, enhances osteoclast differentiation in rat bone marrow culture system. Bone Miner. 19, 215-223 (1992).
26. Pease J, Wang J, Ponath P, Murphy P. The N-terminal extracellular segments of the chemokine receptors CCR1 and CCR3 are determinants for MIP-1α and eotaxin binding, respectively, but a second domain is essential for efficient receptor activation. J. Biol. Chem. 273, 19972-19976 (1998).
27. Hamm H, Gilchrist A. Heterotrimeric G proteins. Curr. Opin. Cell Biol. 8(2), 189-196 (1996).
28. Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br. J. Pharmacol. 147(Suppl 1), S46-55 (2006).
29. Eglen R, Gilchrist A, Reisine T. The use of immortalized cell lines in GPCR screening: the good, bad and ugly. Comb. Chem. High Throughput Screen. 11, 560-565 (2008).
30. Marinissen M, Gutkind J. G-proteincoupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci. 22, 368-376 (2001).
31. Gilchrist A. Modulating G-protein-coupled receptors: from traditional pharmacology to allosterics. Trends Pharmacol. Sci. 28, 431-437 (2007).
32. Nardelli B, Tiffany H, Bong G et al. Characterization of the signal transduction pathway activated in human monocytes and dendritic cells by MPIF-1, a specific ligand for CC chemokine receptor 1. J. Immunol. 162, 435-444 (1999).
33. Tian Y, New D, Yung L et al. Differential chemokine activation of CC chemokine receptor 1-regulated pathways: ligand selective activation of Gα 14-coupled pathways. Eur. J. Immunol. 34, 785-795 (2004).
34. Tian Y, Lee M, Yung L et al. Differential involvement of Ga16 in CC chemokineinduced stimulation of phospholipase Cbeta, ERK, and chemotaxis. Cell Signal. 20, 1179-1189 (2008).
35. 16 in regulating CCR1-induced IKK/NF-aB activity through Raf-1/MEK/ERK, PLCa/ PKC/CaMKII and c-Src signaling cascades.
36. Melnychuk R, Streblow D, Smith P, Hirsch A, Pancheva D, Nelson J. Human cytomegalovirus-encoded G protein-coupled receptor US28 mediates smooth muscle cell migration through Ga12. J. Virol. 78, 8382-8391 (2004).
37. Rosenkilde M, McLean K, Holst P, Schwartz T. The CXC chemokine receptor encoded by herpesvirus saimiri, ECRF3, shows ligand-regulated signaling through Gi, Gq, and G12/13 proteins but constitutive signaling only through Gi and G12/13 proteins. J. Biol. Chem. 279, 32524-32533 (2004).
38. Shepard L, Yang M, Xie P et al. Constitutive activation of NF-kappa B and secretion of interleukin-8 induced by the G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus involve G α(13) and RhoA. J. Biol. Chem. 276, 45979-45987 (2001).
39. Tan W, Martin D, Gutkind J. The Gα13-Rho signaling axis is required for SDF-1- induced migration through CXCR4. J. Biol. Chem. 281, 39542-39549 (2006).
40. Maghazachi A, al-Aoukaty A, Schall T. C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells. Role for G proteins. J. Immunol. 153, 4969-4977 (1994).
41. al-Aoukaty A, Schall T, Maghazachi A. Differential coupling of CC chemokine receptors to multiple heterotrimeric G proteins in human interleukin-2-activated natural killer cells. Blood 87, 4255-4260 (1996).
42. Kim I, Jang S, Sung H, Lee J, Ko J. Differential CCR1-mediated chemotaxis signaling induced by human CC chemokine HCC-4/CCL16 in HOS cells. FEBS Lett. 579, 6044-6048 (2005).
43. Maillet E, Pellegrini N, Valant C et al. A novel, conformation-specific allosteric inhibitor of the tachykinin NK2 receptor (NK2R) with functionally selective properties. FASEB J. 21, 2124-2134 (2007).
44. Rihakova L, Quiniou C, Hamdan F et al. VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297(4), 1009-1118 (2009).
45. Halks-Miller M, Schroeder M, Haroutunian V et al. CCR1 is an early and specific marker of Alzheimer's disease. Ann. Neurol. 54, 638-646 (2003).
46. Potteaux S, Combadière C, Esposito B et al. Chemokine receptor CCR1 disruption in bone marrow cells enhances atherosclerotic lesion development and inflammation in mice. Mol. Med. 11, 16-20 (2005).
47. Horuk R, Shurey S, Ng H et al. CCR1- specific non-peptide antagonist: efficacy in a rabbit allograft rejection model. Immunol. Lett. 76, 193-201 (2001).
48. Vallet S, Anderson K. CCR1 as a target for multiple myeloma. Expert Opin. Ther. Targets 15, 1037-1047 (2011).
49. Norman P. AZD-4818, a chemokine CCR1 antagonist: WO2008103126 and WO2009011653. Expert Opin. Ther. Pat. 19, 1629-1633 (2009).
50. Gladue R, Zwillich S, Clucas A, Brown M. CCR1 antagonists for the treatment of autoimmune diseases. Curr. Opin. Investig. Drugs 5, 499-504 (2004).
51. Gladue R, Tylaska L, Brissette W et al. CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. J. Biol. Chem. 278, 40473-40480 (2003).
52. Horuk R. BX471: a CCR1 antagonist with anti-inflammatory activity in man. Mini Rev. Med. Chem. 5, 791-804 (2005).
53. Sezer O. Myeloma bone disease: recent advances in biology, diagnosis, and treatment. Oncologist 14, 276-283 (2009).
54. Roodman G. Targeting the bone microenvironment in multiple myeloma. J. Bone Miner. Metab. 28, 244-250 (2010).
55. Raab M, Podar K, Breitkreutz I, Richardson P, Anderson K. Multiple myeloma. Lancet 374, 324-339 (2009).
56. Kosmas C, Stamatopoulos K, Stavroyianni N et al. Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire. Leukemia 14, 1718-1726 (2000).
57. Vande Broek I, Vanderkerken K, Van Camp B, Van Riet I. Extravasation and homing mechanisms in multiple myeloma. Clin. Exp. Metastasis 25, 325-334 (2008).
58. Lentzsch S, Gries M, Janz M, Bargou R, Dörken B, Mapara M. Macrophage inflammatory protein 1-α (MIP-1 α) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 101, 3568-3573 (2003).
59. Magrangeas F, Nasser V, Avet-Loiseau H et al. Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease. Blood 101, 4998-5006 (2003).
60. Oba Y, Lee J, Ehrlich L et al. MIP-1a utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Exp Hematol. 33, 272-278 (2005).
61. Terpos E, Politou M, Szydlo R, Goldman J, Apperley J, Rahemtulla A. Serum levels of macrophage inflammatory protein-1 α(MIP-1α) correlate with the extent of bone disease and survival in patients with multiple myeloma. Br. J. Haematol. 123, 106-109. (2003).
62. Vallet S, Pozzi S, Patel K et al. A novel role for CCL3 (MIP-1α) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Leukemia 25, 1174-1181 (2011).
63. Möller C, Strömberg T, Juremalm M, Nilsson K, Nilsson G. Expression and function of chemokine receptors in human multiple myeloma. Leukemia 17, 203-210 (2003).
64. De Vos J, Couderc G, Tarte K et al. Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays. Blood 98, 771-780 (2001).
65. Vande Broek I, Leleu X, Schots R et al. Clinical significance of chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival. Haematologica 91, 200-206 (2006).
66. Choi S, Oba Y, Gazitt Y et al. Antisense inhibition of macrophage inflammatory protein 1-α blocks bone destruction in a model of myeloma bone disease. J. Clin. Invest. 108, 1833-1841 (2001).
67. Menu E, De Leenheer E, De Raeve H et al. Role of CCR1 and CCR5 in homing and growth of multiple myeloma and in the development of osteolytic lesions: a study in the 5TMM model. Clin. Exp. Metastasis 23, 291-300 (2006).
68. Vallet S, Raje N, Ishitsuka K et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood 110, 3744-3752 (2007).
69. Teitelbaum S. Osteoclasts: what do they do and how do they do it? Am. J. Pathol. 170, 427-435 (2007).
70. Väänänen H, Laitala-Leinonen T. Osteoclast lineage and function. Arch. Biochem. Biophys. 473, 132-138 (2008).
71. Roodman G. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655-1664 (2004).
72. Kominsky S, Abdelmagid S, Doucet M, Brady K, Weber K. Macrophage inflammatory protein-1 delta: a novel osteoclast stimulating factor secreted by renal cell carcinoma bone metastasis. Cancer Res. 68, 1261-1266 (2008) .
73. Watanabe T, Kukita T, Kukita A et al. Direct stimulation of osteoclastogenesis by MIP-1α: evidence obtained from studies using RAW264 cell clone highly responsive to RANKL. J. Endocrinol. 180, 193-201 (2004).
74. Scheven B, Milne J, Hunter I, Robins S. Macrophage-inflammatory protein-1a regulates preosteoclast differentiation in vitro. Biochem. Biophys. Res. Commun. 254, 773-778 (1999).
75. Zipp F, Hartung H, Hillert J et al. Blockade of chemokine signaling in patients with multiple sclerosis. Neurology 67, 1880-1883 (2006).
76. Reuss R, Schreiber V, Klein A et al. Nosignificant effect of orally administered chemokine receptor 1 antagonist on intercellular adhesion molecule-3 expression in relapsing-remitting multiple sclerosis patients. Mult. Scler. 16(366-369. (2010) .
77. D'Elios M, Del Prete G, Amedei. Interfering with chemokines and chemokine receptors as potential new therapeutic strategies. Expert Opin. Ther. Patents 18, 309-325 (2008).
78. Gladue R, Brown M. Current status of CCR1 antagonists in clinical trials. Neote, K, Letts G, Moser B (Eds). Birkhäuser Basel, Basel, Switzerland, (2007)
79. Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 43, 3714-3717 (2000).
80. Egan W, Merz K, Baldwin J. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 43, 3867-3877 (2000).
81. Dairaghi D, Zhang P, Wang Y et al. Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose. Clin. Pharmacol. Ther. 89, 726-734 (2011).
82. Conn P, Christopoulos A, Lindsley C. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41-54 (2009). Excellent review on allosteric modulation for anyone working on GPCRs.
83. Sabroe I, Peck M, Van Keulen B et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J. Biol. Chem. 275, 25985-25992 (2000).
84. Kerstjens H, Bjermer L, Eriksson L, Dahlström K, Vestbo J. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients. Respir. Med. 104, 1297-1303 (2010).
85. Liang M, Mallari C, Rosser M et al. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J. Biol. Chem. 275, 19000-19008 (2000).
86. Horuk R, Clayberger C, Krensky A et al. A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J. Biol. Chem. 276, 4199-4204 (2001).
87. Anders H, Vielhauer V, Frink M et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J. Clin. Invest. 109, 251-259 (2002).
88. Lentzsch S, Anderson G, Cuiling L et al. ASH Annual Meeting Abstracts. Blood 106, Abstract 3383 (2005).
89. Oyajobi B, Dairaghi D, Gupta A et al. CCR1 blockade by an orally-available CCR1 antagonist reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease. Blood 116, 3000 (2010).
90. Ribeiro S, Horuk R. The clinical potential of chemokine receptor antagonists. Pharmacol. Ther. 107, 44-58 (2005).
91. Horuk R. Targeting CCR1. In: Chemokine Receptors as Drug Targets. Smit MJ, Lira SA, Leurs R (Eds). Wiley-VCH, Weinheim, Germany, 323-338. (2010)
92. Godessart N. Chemokine receptors: attractive targets for drug discovery. Ann. NY Acad. Sci. 1051, 647-657 (2005).
93. Vergunst C, Gerlag D, von Moltke L et al. 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. 60, 3572-3581 (2009).
94. Pease J, Horuk R. Chemokine receptor antagonists: Part 1. Expert Opin. Ther. Pat. 19, 39-58 (2009).
95. Gladue R, Cole S, Roach M et al. The human specific CCR1 antagonist CP-481,715 inhibits cell infiltration and inflammatory responses in human CCR1 transgenic mice. J. Immunol. 176, 3141-3148. (2006).
96. Clucas A, Shah A, Zhang Y, Chow V, Gladue R. Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715. Clin. Pharmacokinet. 46, 757-766 (2007).
97. Gladue R, Brown M, Zwillich S. CCR1 antagonists: what have we learned from clinical trials. Curr. Top. Med. Chem. 10, 1268-1277 (2010). A 'behind the scenes' perspective on the CCR1 antagonists that have made it in to the clinic. The authors describe the evidence that supports a role for CCR1 in RA, MS and COPD, the results from clinical trials, and provide informed analysis on what has been learned.
98. Merritt J, Liu J, Quadros E et al. Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists. J. Med. Chem. 52, 1295-1301 (2009).
99. Merritt J, James R, Paradkar V et al. Novel pyrrolidine heterocycles as CCR1 antagonists. Bioorg. Med. Chem. Lett. 20, 5477-5479 (2010).
100. Hesselgesser J, Ng H, Liang M et al. Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor. J. Biol. Chem. 273, 15687-15692 (1998).
101. Revesz L, Bollbuck B, Buhl T et al. Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis. Bioorg. Med. Chem. Lett. 15, 5160-5164 (2005).
102. Xie Y, Sircar I, Lake K et al. Identification of novel series of human CCR1 antagonists. Bioorg. Med. Chem. Lett. 18, 2215-2221 (2008).
103. Xie Y, Lake K, Ligsay K et al. Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists. Bioorg. Med. Chem. Lett. 17, 3367-3372 (2007).
104. Saeki T, Naya A. CCR1 chemokine receptor antagonist. Curr. Pharm. Des. 9, 1201-1208 (2003).
105. Vaidehi N, Schlyer S, Trabanino R et al. Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation. J. Biol. Chem. 281, 27613-27620 (2006).
106. Wise E, Duchesnes C, da Fonseca P, Allen R, Williams T, Pease J. Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation. J. Biol. Chem. 282, 27935-27943 (2007).
107. Kondru R, Zhang J, Ji C et al. Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Mol. Pharmacol. 73, 789-800 (2008).
108. Gilchrist A, Blackmer T. G-protein-coupled receptor pharmacology: examining the edges between theory and proof. Curr. Opin. Drug Discov. Devel. 10, 446-451 (2007).
109. Watson C, Jenkinson S, Kazmierski W, Kenakin T. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol. Pharmacol. 67, 1268-1282 (2005).
110. Schall T, Proudfoot A. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat. Rev. Immunol. 11, 355-363 (2011).
111. Onuffer J, McCarrick M, Dunning L et al. Structure function differences in nonpeptide CCR1 antagonists for human and mouse CCR1. J. Immunol. 170, 1910-1916 (2003).
112. Borregaard J, Skov L, Wang L et al. Evaluation of the effect of the specific CCR1 antagonist CP-481715 on the clinical and cellular responses observed following epicutaneous nickel challenge in human subjects. Contact Dermatitis. 59, 212-219 (2008).
113. Haringman J, Kraan M, Smeets T, Zwinderman K, Tak P. Chemokine blockade and chronic inflammatory disease: proof of concept in patients with rheumatoid arthritis. Ann. Rheum. Dis. 62, 715-721 (2003).
114. AstraZeneca: WO/2008/103126 (2008).
115. AstraZeneca: WO/2009/011653 (2009).
116. AstraZeneca: WO/2009/011655 (2009).
117. Bristol-Myers Squibb: WO/2009/158452 (2009).
118. Bristol-Myers Squibb: WO/2011/044309 (2011).
119. ChemoCentryx, Inc.: US7449576 (2008).
120. Millennium Pharmaceuticals, Inc.: WO/2004/043965 (2004).
121. Boehringer Ingelheim: WO/2009/137338 (2009).
122. Boehringer Ingelheim: WO/2010/036632 (2010).
123. Boehringer Ingelheim: WO/2009/134666 (2009).
124. Chemokine receptors. www.iuphar-db.org/DATABASE/Family IntroductionForward?familyId=14 (Accessed on 10 September 2011)
125. Molinspiration cheminformatics. www.molinspiration.com (Accessed on 16 September 2011)
126. Australian New Zealand Clinical Trials Registry. www.anzctr.org.au/ ACTRN12609000788279.aspx (Accessed on 16 September 2011)
127. Proof-of-concept study with BMS-817399 to treat moderate to severe rheumatoid arthritis (RA). http://clinicaltrials.gov/ct2/show/NCT01404585 (Accessed on 16 September 2011)
128. Study to investigate the efficacy of a non-hormonal drug against endometriosis associated pelvic pain. www.clinicaltrials.gov/ct2/show/ NCT00185341 (Accessed on 6 September 2011)
129. A study to evaluate the safety and efficacy of CCX354-C in subjects with rheumatoid arthritis partially responsive to methotrexate therapy (CARAT-2) http://clinicaltrials.gov/ct2/show/NCT01242917
130. ChemoCentryx CCR1 program. www.chemocentryx.com/product/CCR1.html (Accessed on 6 September 2011)