Chemokine receptor antagonists: Part 1

Expert Opinion on Therapeutic Patents

Volumn 19, Issue 1, 2009, Pages 39-58

  Pease, James E ^b   Horuk, Richard ^a  

^a TOURO UNIVERSITY CALIFORNIA   (United States)

^b NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

Antagonism; Chemokine receptors; Chemokines; GPCRs

Indexed keywords

1 [5 CHLORO 2 [2 [4 (4 FLUOROBENZYL) 2 METHYL 1 PIPERAZINYL] 2 OXOETHOXY]PHENYL]UREA; A 122058; BMS 570520; CCR 2; CCR 9; CCX 105; CCX 140; CCX 469; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR1; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CCR3; CHEMOKINE RECEPTOR CCR4; COMPOUND 8C; CP 481715; CP 781 715; DPC 168; GSK 766994; GW 701897 B; INCB 3344; ISOQUINOLINE DERIVATIVE; KW 0761; MK 0812; MLN 3897; NAPHTHALENE DERIVATIVE; PF 4136309; PIPERIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; QUINAZOLINE DERIVATIVE; QUINOLINE DERIVATIVE; RS 504393; SB 328437; SULFONAMIDE; UNCLASSIFIED DRUG; YM 344031; YM 355179;

ALLERGIC ENCEPHALOMYELITIS; ALLERGIC RHINITIS; CANCER RELAPSE; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG HALF LIFE; DRUG RECEPTOR BINDING; HUMAN; IC 50; INFLAMMATION; MAXIMUM PLASMA CONCENTRATION; MULTIPLE SCLEROSIS; NONHUMAN; PAIN; PATENT; PEER REVIEW; RESTENOSIS; REVIEW; RHEUMATOID ARTHRITIS; SKIN ALLERGY; T CELL LEUKEMIA; T CELL LYMPHOMA;

ANIMALS; CHEMOKINES, CC; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; PATENTS AS TOPIC; RECEPTORS, CCR1; RECEPTORS, CCR2; RECEPTORS, CCR3; RECEPTORS, CCR4;

EID: 67649425653     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543770802641346     Document Type: Review

References (165)

1. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity 2000;12:121-127 (Pubitemid 30398626)
2. van Creveld S, Paulssen MM. Significance of clotting factors in blood-platelets, in normal and pathological conditions. Lancet 1951;2:242-244
3. Murphy PM, Baggiolini M, Charo IF, et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000;52:145-176
4. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. 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. Baggiolini M. Chemokines and leukocyte traffic. Nature 1998;392:565-568 (Pubitemid 28207705)
6. Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2:108-115 (Pubitemid 33707927)
7. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996;272:872-877
8. Doranz BJ, Rucker J, Yi YJ, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the b-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 1996;85:1149-1158
9. Ribeiro S, Horuk R. Chemokine receptor antagonists from the bench to the clinic. In: Hannan A, Engelhardt B, Editors, Weinheim: Wiley-VCH; 2005
10. Ribeiro S, Horuk R. The clinical potential of chemokine receptor antagonists. Pharmacol Ther 2005;107:44-58 (Pubitemid 40803508)
11. MacArthur RD, Novak RM. Reviews of anti-infective agents: maraviroc: the first of a new class of antiretroviral agents. Clin Infect Dis 2008;47:236-241
12. Schwarz MK, Wells TNC. Recent developments in modulating chemokine networks. Expert Opin Ther Pat 1999;9:1471-1489 (Pubitemid 29515553)
13. Pease JE, Williams TJ. The attraction of chemokines as a target for specific anti-inflammatory therapy. Br J Pharmacol 2006;147 (Suppl 1):S212-21 (Pubitemid 43077279)
14. Neote K, DiGregorio D, Mak JY, et al. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell 1993;72:415-425 (Pubitemid 23059411)
15. Gao JL, Kuhns DB, Tiffany HL, et al. Structure and functional expression of the human macrophage inflammatory protein 1 alpha/RANTES receptor. J Exp Med 1993;177:1421-1427 (Pubitemid 23117132)
16. Weber C, Weber KS, Klier C, et al. Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells. Blood 2001;97:1144-1146 (Pubitemid 32154307)
17. Broxmeyer HE, Cooper S, Hangoc G, et al. Dominant Myelopoietic Effector Functions Mediated by Chemokine Receptor CCR1. J Exp Med 1999;189:1987-1992 (Pubitemid 29295898)
18. Gao JL, Wynn TA, Chang Y, et al. Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J Exp Med 1997;185:1959-1968 (Pubitemid 27247082)
19. Gerard C, Frossard JL, Bhatia M, et al. Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. J Clin Invest 1997;100:2022-2027 (Pubitemid 27459356)
20. Barnes DA, Tse J, Kaufhold M, et al. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest 1998;101:2910-2919 (Pubitemid 28294601)
21. Trebst C, Sorensen TL, Kivisakk P, et al. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am J Pathol 2001;159:1701-1710 (Pubitemid 33062513)
22. Rottman JB, Slavin AJ, Silva R, et al. Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol 2000;30:2372-2377 (Pubitemid 30655773)
23. Pattison JM, Nelson PJ, Huie P, et al. RANTES chemokine expression in transplant-associated accelerated atherosclerosis. J Heart Lung Transplant 1996;15:1194-1199 (Pubitemid 26428394)
24. Gao W, Topham PS, King JA, et al. Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection. J Clin Invest 2000;105:35-44 (Pubitemid 30036385)
25. Sabroe I, Hartnell A, Jopling LA, et al. Differential Regulation of Eosinophil Chemokine Signaling Via CCR3 and Non-CCR3 Pathways. J Immunol 1999;162:2946-2955 (Pubitemid 29309323)
26. Toda M, Dawson M, Nakamura T, et al. Impact of Engagement of FcepsilonRI and CC chemokine receptor 1 on mast cell activation and motility. J Biol Chem 2004;279:48443-48448 (Pubitemid 39541002)
27. 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 2000;275:19000-19008 (Pubitemid 30422866)
28. Horuk R, Clayberger C, Krensky AM, et al. A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J Biol Chem 2001;276:4199-4204 (Pubitemid 37371506)
29. Anders HJ, Vielhauer V, Frink M, et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. J Clin Invest 2002;109:251-259 (Pubitemid 34083745)
30. 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 2006;23:291-300 (Pubitemid 44777569)
31. Zipp F, Hartung HP, Hillert J, et al. Blockade of chemokine signaling in patients with multiple sclerosis. Neurology 2006;67:1880-1883 (Pubitemid 44900777)
32. Gladue RP, Tylaska LA, Brissette WH, et al. CP-481,715: A potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. J Biol Chem 2003;278:40473-40480
33. Brown MF, Avery M, Brissette WH, et al. Novel CCR1 antagonists with improved metabolic stability. Bioorg Med Chem Lett 2004;14:2175-2179 (Pubitemid 38481385)
34. Kath JC, Brissette WH, Brown MF, et al. Potent small molecule CCR1 antagonists. Bioorg Med Chem Lett 2004;14:2169-2173 (Pubitemid 38481384)
35. Kath JC, DiRico AP, Gladue RP, et al. The discovery of structurally novel CCR1 antagonists derived from a hydroxyethylene peptide isostere template. Bioorg Med Chem Lett 2004;14:2163-2167 (Pubitemid 38481383)
36. Gladue RP, Cole SH, Roach ML, et al. 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 (Pubitemid 43306976)
37. Brown MF, Bahnck KB, Blumberg LC, et al. Piperazinyl CCR1 antagonists-optimization of human liver microsome stability. Bioorg Med Chem Lett 2007;17:3109-3112 (Pubitemid 46702621)
38. Brown MF, Kath JC, Poss CS. Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-alpha binding to its CCR1 receptor. WO199838167; 1998
39. Brown MF, Poss CS. Heterocyclic amide derivatives useful as inhibitors of MIP-1alpha binding to CCR1 receptors. WO200157023; 2001
40. Brown MF, Poss CS. Quinoxalinyl amide derivatives. US6548671; 2003
41. Blumberg LC, Brown MF, Gladue RP, et al. Piperazine derivatives. US6649611; 2003
42. Kath JC, Brown MF, Poss CS. Dihydroxyhexanoic acid derivatives. US6673801; 2004
43. Hayward MA, Sulfonic acid derivatives. US6974817; 2005
44. Gladue RP, Zwillich SH, Clucas AT, Brown MF. CCR1 antagonists for the treatment of autoimmune diseases. Curr Opin Investig Drugs 2004;5:499-504
45. Luly J, Nakasuto Y, Oshima E. Chemokine receptor antagonists and methods of use thereof. US6288083; 2001
46. Luly J, Nakasuto Y, Oshima E, et al. Chemokine receptor antagonists and methods of use thereof. US6509346; 2003
47. Luly J, Nakasuto Y, Oshima E, et al. Chemokine receptor antagonists and methods of use thereof. US6503926; 2003
48. Carson KG, Harriman GCB. CCR1 antagonists and methods of use therefor. US20040106639; 2004
49. Carson KG, Harriman GCB. CCR1 antagonists and methods of use therefor. US20050288319; 2005
50. Luly J, Nakasuto Y, Oshima E, et al. Chemokine receptor antagonists and methods of use thereof. US7271176; 2007
51. IDdb. MLN-3897 Update. The Investigational Drugs Database Drug Report, 2004. Available from: http://www.iddb3.com/iddb3/iddb3-2/reports.display?id= 37473&template=Drug&i-query-id=4471271
52. Hesselgesser J, Ng HP, Liang M, et al. Identification and characterization of small molecule functional antagonists of the ccr1 chemokine receptor. J Biol Chem 1998;273:15687-15692 (Pubitemid 28298186)
53. Ng HP, May K, Bauman JG, et al. Discovery of novel non-peptide CCR1 receptor antagonists. J Med Chem 1999;42:4680-4694 (Pubitemid 29530021)
54. 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 2007;110:3744-3752 (Pubitemid 350159645)
55. Vann L. End of 2007 brings Extra Activity. Autoimmune Drug Focus 2007;37:1
56. McMaster BE, Anti-inflammatory compositions and methods of use. US6727241; 2003
57. Pennell AMK, Aggen JB, Wright JJK, et al. 1-Aryl-4-substituted piperazines derivatives for use as CCR1 antagonists for the treatment of inflammation and immune disorders. WO2003105853; 2003
58. Pennell AMK, Aggen JB, Wright JJK, et al. Substituted piperazines. US7157464; 2007
59. Zhang P, Pennell AMK, W C, et al. Piperidine derivatives and methods of use. US20070088036; 2007
60. Zhang P, Pennell AMK, W C, et al. Piperidine derivatives and methods of use. US20070093467; 2007
61. Zhang P, Pennell AMK, Wright JJK, et al. Monocyclic and bicyclic compounds and methods of use. US20070066583; 2007
62. Zhang P, Pennell AMK, Wright JJK, et al. Azaindazole compounds and methods of use. US20070010524; 2007
63. Zhang P, Pennell AMK, Wright JJK, et al. Azaindazole compounds and methods of use. US20070010523; 2007
64. Naya A, Owada Y, Saeki T, et al. Chemokine receptor antagonists. US6140338; 1999
65. Naya A, Sagara Y, Ohwaki K, et al. Design, synthesis, and discovery of a novel CCR1 antagonist. J Med Chem 2001;44:1429-1435 (Pubitemid 32852119)
66. Naya A, Kobayashi K, Ishikawa M, et al. Discovery of a novel CCR3 selective antagonist. Bioorg Med Chem Lett 2001;11:1219-1223 (Pubitemid 32406089)
67. Saeki T, Naya A. CCR1 chemokine receptor antagonist. Curr Pharm Des 2003;9:1201-1208 (Pubitemid 36582255)
68. Xie YF, Sircar I, Lake K, et al. Identification of novel series of human CCR1 antagonists. Bioorg Med Chem Lett 2008;18:2215-2221
69. Xie YF, Lake K, Ligsay K, et al. Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists. Bioorg Med Chem Lett 2007;17:3367-3372 (Pubitemid 46819030)
70. Bollbuck B, Eder J, Heng R, et al. 1-(4-benzyl-piperazin-1-yl)-3-phenyl- propenone derivatives. WO2004037796; 2004
71. Revesz L, Bollbuck B, Buhl T, et al. Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis. Bioorg Med Chem Lett 2005;15:5160-5164 (Pubitemid 41463639)
72. Charo IF, Myers SJ, Herman A, et al. Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci USA 1994;91:2752-2756 (Pubitemid 24139426)
73. Hancock WW, Gao W, Faia KL, Csizmadia V. Chemokines and their receptors in allograft rejection. Curr Opin Immunol 2000;12:511-516 (Pubitemid 30701145)
74. Szekanecz Z, Szucs G, Szanto S, Koch AE. Chemokines in rheumatic diseases. Curr Drug Targets 2006;7:91-102
75. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006;354:610-621
76. Taylor PC, Peters AM, Paleolog E, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum 2000;43:38-47 (Pubitemid 30368211)
77. Min DJ, Cho ML, Lee SH, et al. Augmented production of chemokines by the interaction of type II collagen-reactive T cells with rheumatoid synovial fibroblasts. Arthritis Rheum 2004;50:1146-1155 (Pubitemid 38480824)
78. Katschke KJ Jr, Rottman JB, Ruth JH, et al. Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 2001;44:1022-1032 (Pubitemid 32433606)
79. Ellingsen T, Hornung N, Moller BK, et al. Differential effect of methotrexate on the increased CCR2 density on circulating CD4 T lymphocytes and monocytes in active chronic rheumatoid arthritis, with a down regulation only on monocytes in responders. Ann Rheum Dis 2007;66:151-157 (Pubitemid 46226046)
80. Karpus WJ, Kennedy KJ. MIP-1alpha and MCP-1 differentially regulate acute and relapsing autoimmune encephalomyelitis as well as Th1/Th2 lymphocyte differentiation. J Leukoc Biol 1997;62:681-687 (Pubitemid 27519780)
81. Gosling J, Slaymaker S, Gu L, et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 1999;103:773-778 (Pubitemid 29152622)
82. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998;394:894-897 (Pubitemid 28410911)
83. Butora G, Jiao R, Parsons WH, et al. 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 (Pubitemid 46898824)
84. Butora G, Morriello GJ, Kothandaraman S, et al. 4-Amino-2-alkyl- butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties. Bioorg Med Chem Lett 2006;16:4715-4722 (Pubitemid 44175870)
85. Yang L, Butora G, Jiao RX, et al. Discovery of 3-piperidinyl-1- cyclopentanecarboxamide as a novel scaffold for highly potent CC chemokine receptor 2 antagonists. J Med Chem 2007;50:2609-2611 (Pubitemid 46896068)
86. Yang L, Zhou C, Guo L, et al. Discovery of 3,5-bis(trifluoromethyl)benzyl L-arylglycinamide based potent CCR2 antagonists. Bioorg Med Chem Lett 2006;16:3735-3739 (Pubitemid 44137244)
87. Pinkerton AB, Huang D, Cube RV, et al. Diaryl substituted pyrazoles as potent CCR2 receptor antagonists. Bioorg Med Chem Lett 2007;17:807-813 (Pubitemid 46127636)
88. Pasternak A, Goble SD, Doss GA, et al. Conformational studies of 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists leading to new spirocyclic antagonists. Bioorg Med Chem Lett 2008;18:1374-1377 (Pubitemid 351226540)
89. Pasternak A, Goble SD, Vicario PP, et al. Potent heteroarylpiperidine and carboxyphenylpiperidine 1-alkyl-cyclopentane carboxamide CCR2 antagonists. Bioorg Med Chem Lett 2008;18:994-998 (Pubitemid 351179351)
90. Pasternak A, Marino D, Vicario PP, et al. Novel, orally bioavailable gamma-aminoamide CC chemokine receptor 2 (CCR2) antagonists. J Med Chem 2006;49:4801-4804 (Pubitemid 44201036)
91. Yang L, Butora G, Parsons WH, Pasternak A. Cyclopentyl modulators of chemokine receptor activity. US20050049222; 2005
92. Jiao R, Butora G, Goble SD, et al. Tetrahydropyranyl cyclopentyl tetrahydropyridopyridine modulators of chemokine receptor activity. US20050107422; 2005
93. Abbadie C, Lindia JA, Wang H. CCR2 antagonists for treatment of neuropathic pain. US20060205761; 2006
94. DeMartino J, Akiyama T, Struthers M, et al. Tetrahydropyranyl cyclopentyl tetrahydropyridopyridine modulators of chemokine receptor activity. US20060030582; 2006
95. Butora G, Pasternak A, Yang L, Zhou C, Gamma-aminoamide modulators of chemokine receptor activity. US7247725; 2007
96. Yang L, Mills SG, Zhou C, et al. 2,6-disubstituted piperidines as modulators. US7410961; 2008
97. Goble SD, Pasternak A, Mills SG, et al. Tetrahydropyranyl cyclopentyl heterocyclic amide modulators of chemokine receptor activity. US7393844; 2008
98. Forrest MLJ, Demartino JA, Flicker MR, et al. Drug Combination Therapy and Pharmaceutical Compositions for Treating Inflammatory Disorders. US20080194548; 2008
99. Yang L, Jiao RX, Moyes C, et al. The discovery of MK-0812, a potent and selective CCR2 antagonist. American Chemical Society Meeting. Chicago: 2007. Available from: www.acsmedchem.org/mediabstracts2007.pdf
100. Beaulieu A, Hasler F, Martin Mola E, et al. The efficacy and safety of a CCR2 receptor antagonist in the treatment of rheumatoid arthritis (RA). Ann Rheum Dis 2006;65 (Suppl II):175. Available from: http://www.abstracts2view.com/ eular/search.php?search=do&intMaxHits=10&where[]=&andornot[]= &query=CCR2+antagonist.
101. Braddock M. 11th Annual Inflammatory and Immune Diseases Drug Discovery and Development Summit 12-13 March 2007, San Francisco, USA. Expert Opin Investig Drugs 2007;16:909-917
102. Braddock M. Advances in Anti-Inflammatory Therapeutics: 20-21 November 2006, London, UK. Expert Opin Investig Drugs 2007;16:257-261
103. Imai M, Shiota T, Kataoka K, et al. Small molecule inhibitors of the CCR2b receptor. Part 1: Discovery and optimization of homopiperazine derivatives. Bioorg Med Chem Lett 2004;14:5407-5411
104. Moree WJ, Kataoka K, Ramirez-Weinhouse MM, et al. Small molecule antagonists of the CCR2b receptor. Part 2: Discovery process and initial structure-activity relationships of diamine derivatives. Bioorg Med Chem Lett 2004;14:5413-5416
105. Moree WJ, Kataoka K, Ramirez-Weinhouse MM, et al. Potent antagonists of the CCR2b receptor. Part 3: SAR of the (R)-3-aminopyrrolidine series. Bioorg Med Chem Lett 2008;18:1869-1873
106. Charvat TT, Hu C, Jin J, et al. Triazolyl pyridyl benzenesulfonamides. US20080039504; 2008
107. Available from: http://www.chemocentryx.com/product/CCR2.html.
108. Mirzadegan T, Diehl F, Ebi B, et al. Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem 2000;275:25562-25571 (Pubitemid 30687060)
109. Berkhout TA, Blaney FE, Bridges AM, et al. CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach. J Med Chem 2003;46:4070-4086 (Pubitemid 37122451)
110. Cherney RJ, Mo R, Meyer DT, et al. Discovery of disubstituted cyclohexanes as a new class of CC chemokine receptor 2 antagonists. J Med Chem 2008;51:721-724 (Pubitemid 351304681)
111. Cherney RJ, Nelson DJ, Lo YC, et al. Synthesis and evaluation of cis-3,4-disubstituted piperidines as potent CC chemokine receptor 2 (CCR2) antagonists. Bioorg Med Chem Lett 2008;18:5063-5065
112. Clark RD, Caroon JM, Kluge AF, et al. Synthesis and antihypertensive activity of 4′-substituted spiro[4H-3,1-benzoxazine-4,4′-piperidin]- 2(1H)-ones. J Med Chem 1983;26:657-661
113. Strader CD, Fong TM, Tota MR, et al. Structure and function of G protein-coupled receptors. Annu Rev Biochem 1994;63:101-132 (Pubitemid 24218630)
114. Xue C, Feng H, Cao G, et al. 3-Cycloalkylaminopyrrolidine derivatives as modulators of chemokine receptors. WO2004050024; 2004
115. Brodmerkel CM, Huber R, Covington M, et al. Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344. J Immunol 2005;175:5370-5378 (Pubitemid 41456423)
116. Xue C, Metcalf BW, Han AQ, et al. Salts of N-[2-({(3R)-1-[trans-4- hydroxy-4-(6-methoxypyridin-3-yl)-cyclohexyl] pyrrolidin-3-yl}amino)-2-oxoethyl] -3-(trifluoromethyl)benzamide. US20060111404; 2006
117. Xue C, Zheng C, Cao G, et al. 3-(4-heteroarylcyclohexylamino) cyclopentanecarboxamides as modulators of chemokine receptors. US7307086; 2007
118. Forbes IT, Cooper DG, Dodds EK, et al. CCR2B receptor antagonists: conversion of a weak HTS hit to a potent lead compound. Bioorg Med Chem Lett 2000;10:1803-1806 (Pubitemid 30657610)
119. Witherington J, Bordas V, Cooper DG, et al. Conformationally restricted indolopiperidine derivatives as potent CCR2B receptor antagonists. Bioorg Med Chem Lett 2001;11:2177-2180 (Pubitemid 32763026)
120. Van Lomen G, Doyon J, Coesemans E, et al. 2-Mercaptoimidazoles, a new class of potent CCR2 antagonists. Bioorg Med Chem Lett 2005;15:497-500 (Pubitemid 40143114)
121. Lagu B, Gerchak C, Pan M, et al. Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma. Bioorg Med Chem Lett 2007;17:4382-4386 (Pubitemid 47021372)
122. Xia M, Hou C, Demong D, et al. Substituted dipiperidine alcohols as potent CCR2 antagonists. Bioorg Med Chem Lett 2008;18:3562-3564 (Pubitemid 351787562)
123. Xia M, Hou C, DeMong DE, et al. Synthesis, structure-activity relationship and in vivo antiinflammatory efficacy of substituted dipiperidines as CCR2 antagonists. J Med Chem 2007;50:5561-5563 (Pubitemid 350106010)
124. Xia M, Hou C, Pollack S, et al. Synthesis and biological evaluation of phenyl piperidine derivatives as CCR2 antagonists. Bioorg Med Chem Lett 2007;17:5964-5968 (Pubitemid 47446199)
125. Kettle JG, Faull AW, Barker AJ, et al. N-Benzylindole-2-carboxylic acids: potent functional antagonists of the CCR2b chemokine receptor. Bioorg Med Chem Lett 2004;14:405-408 (Pubitemid 38045133)
126. Ponath PD, Qin S, Post TW, et al. Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. J Exp Med 1996;183:2437-2448 (Pubitemid 26192353)
127. Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997;277:2005-2007 (Pubitemid 27449145)
128. Uguccioni M, Mackay CR, 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 1997;100:1137-1143 (Pubitemid 27386297)
129. Romagnani P, De Paulis A, Beltrame C, et al. Tryptase-chymase double-positive human mast cells express the eotaxin receptor CCR3 and are attracted by CCR3-binding chemokines. Am J Pathol 1999;155:1195-1204 (Pubitemid 29488927)
130. Fulkerson PC, Fischetti CA, McBride ML, et al. A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation. Proc Natl Acad Sci USA 2006;103:16418-16423 (Pubitemid 44715211)
131. Sabroe I, Peck MJ, Van Keulen BJ, 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 2000;275:25985-25992 (Pubitemid 30676638)
132. de Mendonca FL, da Fonseca PC, Phillips RM, et al. Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UCB 35625, a small molecule chemokine receptor antagonist. J Biol Chem 2005;280:4808-4816 (Pubitemid 40288653)
133. Wise EL, Duchesnes C, Da Fonseca PC, et al. Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation. J Biol Chem 2007;282:27935-27943 (Pubitemid 47529544)
134. Pegurier C, Collart P, Danhaive P, et al. Pyrazolone methylamino piperidine derivatives as novel CCR3 antagonists. Bioorg Med Chem Lett 2007;17:4228-4231 (Pubitemid 47021396)
135. White JR, Lee JM, Dede K, et al. Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration. J Biol Chem 2000;275:36626-36631 (Pubitemid 32002063)
136. Dhanak D, Christmann LT, Darcy MG, et al. Discovery of potent and selective phenylalanine derived CCR3 antagonists. Part 1. Bioorg Med Chem Lett 2001;11:1441-1444 (Pubitemid 32510839)
137. Dhanak D, Christmann LT, Darcy MG, et al. Discovery of potent and selective phenylalanine derived CCR3 receptor antagonists. Part 2. Bioorg Med Chem Lett 2001;11:1445-1450 (Pubitemid 32510840)
138. Varnes JG, Gardner DS, Santella JB 3rd, et al. Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists. Bioorg Med Chem Lett 2004;14:1645-1649
139. De Lucca GV, Kim UT, Vargo BJ, et al. Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency. J Med Chem 2005;48:2194-2211 (Pubitemid 40396347)
140. Pruitt JR, Batt DG, Wacker DA, et al. CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity. Bioorg Med Chem Lett 2007;17:2992-2997 (Pubitemid 46702643)
141. Sato I, Morihira K, Inami H, et al. Synthesis and structure-activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl] piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists. Bioorg Med Chem 2008;16:144-156
142. Sato I, Morihira K, Inami H, et al. Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition. Bioorg Med Chem 2008;16:8607-8618
143. Suzuki K, Morokata T, Morihira K, et al. In vitro and in vivo characterization of a novel CCR3 antagonist, YM-344031. Biochem Biophys Res Commun 2006;339:1217-1223
144. Morokata T, Suzuki K, Masunaga Y, et al. A novel, selective, and orally available antagonist for CC chemokine receptor 3. J Pharmacol Exp Ther 2006;317:244-250
145. Warrior U, McKeegan EM, Rottinghaus SM, et al. Identification and characterization of novel antagonists of the CCR3 receptor. J Biomol Screen 2003;8:324-331 (Pubitemid 40503611)
146. Ting PC, Lee JF, Wu J, et al. The synthesis of substituted bipiperidine amide compounds as CCR3 antagonists. Bioorg Med Chem Lett 2005;15:1375-1378 (Pubitemid 40268995)
147. Ting PC, Umland SP, Aslanian R, et al. The synthesis of substituted bipiperidine amide compounds as CCR3 ligands: antagonists versus agonists. Bioorg Med Chem Lett 2005;15:3020-3023 (Pubitemid 40755189)
148. Naya A, Kobayashi K, Ishikawa M, et al. Structure-Activity Relationships of 2-(Benzothiazolylthio)acetamide Class of CCR3 Selective Antagonist. Chem Pharm Bull (Tokyo) 2003;51:697-701 (Pubitemid 41672734)
149. Murdoch RD. Oral presentation, 4th James Black Conference, The Challenges of Drug Discovery & Development. University of Hertfordshire, 2006
150. Fryer AD, Stein LH, Nie Z, et al. Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J Clin Invest 2006;116:228-236 (Pubitemid 43121808)
151. Pilette C, Francis JN, Till SJ, Durham SR. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Eur Respir J 2004;23:876-884 (Pubitemid 38807362)
152. Bochner BS, Hudson SA, Xiao HQ, Liu MC. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J Allergy Clin Immunol 2003;112:930-934 (Pubitemid 37412061)
153. Lloyd CM, Delaney T, Nguyen T, et al. 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 (Pubitemid 30060916)
154. Conroy DM, Jopling LA, Lloyd CM, et al. CCR4 blockade does not inhibit allergic airways inflammation. J Leukoc Biol 2003;74:558-563 (Pubitemid 38040383)
155. Chvatchko Y, Hoogewerf AJ, Meyer A, et al. A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J Exp Med 2000;191:1755-1764 (Pubitemid 30331572)
156. Schuh JM, Power CA, Proudfoot AE, et al. Airway hyperresponsiveness, but
157. Purandare AV, Gao A, Wan H, et al. Identification of chemokine receptor CCR4 antagonist. Bioorg Med Chem Lett 2005;15:2669-2672 (Pubitemid 40615009)
158. Purandare AV, Wan H, Gao A, et al. Optimization of CCR4 antagonists: side-chain exploration. Bioorg Med Chem Lett 2006;16:204-207 (Pubitemid 41625671)
159. Purandare AV, Wan H, Somerville JE, et al. Core exploration in optimization of chemokine receptor CCR4 antagonists. Bioorg Med Chem Lett 2007;17:679-682 (Pubitemid 46108567)
160. Wang X, Xu F, Xu Q, et al. Optimization of 2-aminothiazole derivatives as CCR4 antagonists. Bioorg Med Chem Lett 2006;16:2800-2803
161. Burdi DF, Chi S, Mattia K, et al. Small molecule antagonists of the CC chemokine receptor 4 (CCR4). Bioorg Med Chem Lett 2007;17:3141-3145 (Pubitemid 46702615)
162. Yokoyama K, Ishikawa N, Igarashi S, et al. Discovery of potent CCR4 antagonists: Synthesis and structure-activity relationship study of 2,4-diaminoquinazolines. Bioorg Med Chem 2008;16:7021-7032
163. Yokoyama K, Ishikawa N, Igarashi S, et al. Potent CCR4 antagonists: Synthesis, evaluation, and docking study of 2,4-diaminoquinazolines. Bioorg Med Chem 2008;16:7968-7974
164. Kuhn CF, Bazin M, Philippe L, et al. Bipiperidinyl carboxylic acid amides as potent, selective, and functionally active CCR4 antagonists. Chem Biol Drug Des 2007;70:268-272 (Pubitemid 47305399)
165. Allen S, Newhouse B, Anderson AS, et al. Discovery and SAR of trisubstituted thiazolidinones as CCR4 antagonists. Bioorg Med Chem Lett 2004;14:1619-1624 (Pubitemid 38340652)