Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency

Journal of Medicinal Chemistry

Volumn 48, Issue 6, 2005, Pages 2194-2211

  De Lucca, George V ^a   Ui, Tae Kim ^a   Vargo, Brian J ^a   Duncia, John V ^a   Santella III, Joseph B ^a   Gardner, Daniel S ^a   Zheng, Changsheng ^a   Liauw, Ann ^a   Wang, Zhang ^a   Emmett, George ^a   Wacker, Dean A ^a   Welch, Patricia K ^a   Covington, Maryanne ^a   Stowell, Nicole C ^a   Wadman, Eric A ^a   Das, Anuk M ^a   Davies, Paul ^a   Yeleswaram, Swamy ^a   Graden, Danielle M ^a   Solomon, Kimberly A ^a   Newton, Robert C ^a   Trainor, George L ^a   Decicco, Carl P ^a   Ko, Soo S ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 [[3 (4 FLUOROBENZYL)PIPERIDIN 1 YL] METHYL]CYCLOHEXYL] 3 (3 ACETYLPHENYL)UREA; 1 [2 [[3 (4 FLUOROBENZYL)PIPERIDIN 1 YL] METHYL]CYCLOHEXYL] 3 (5 ACETYL 4 METHYLTHIAZOL 2 YL)UREA; 1 [2 [[3 (4 FLUOROBENZYL)PIPERIDIN 1 YL] METHYL]CYCLOHEXYL] 3 [3 (1 METHYL 1H TETRAZOL 5 YL)PHENYL]UREA; 3 BENZYLPIPERIDINE; 4 BENZYLPIPERIDINE; CHEMOKINE RECEPTOR ANTAGONIST; CHEMOKINE RECEPTOR CCR3; EOTAXIN; PIPERIDINE DERIVATIVE; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ALLERGIC ASTHMA; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOAVAILABILITY; CHEMOTAXIS; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; EOSINOPHIL; HUMAN; HUMAN CELL; IC 50; LUNG; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; BIOLOGICAL AVAILABILITY; CACO-2 CELLS; CALCIUM; CHEMOTAXIS, LEUKOCYTE; CHO CELLS; CRICETINAE; CYCLOHEXANES; EOSINOPHILS; FEMALE; HUMANS; HYPERSENSITIVITY; INFLAMMATION; MALE; MICE; MICE, INBRED BALB C; MICE, INBRED C57BL; PERMEABILITY; PHENYLUREA COMPOUNDS; PIPERIDINES; RECEPTORS, CHEMOKINE; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 20144365483     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049530m     Document Type: Article

References (74)

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25. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
26. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
27. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
28. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
29. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
30. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
31. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
32. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
33. There are several recent reviews that detail the role of chemokines, chemokine receptors, and eosinophils in asthma and inflammation. For example, see: (a) Ramshaw, H. S.; Woodcock, J. M.; Bagley, J.; McClure, B. J.; Hercus, T. R.; Lopez, A. F. New approaches in the treatment of asthma. Immunol. Cell Biol. 2001, 79, 154-159. (b) Lukacs, N. W.; Tekkanat, K. K. Role of chemokines in asthmatic airway inflammation. Immunol. Rev. 2000, 177, 21-30. (c) Bertrand, C. P.; Ponath, P. D. CCR3 blockade as a new therapy for asthma. Expert Opin. Invest. Drugs 2000, 9, 43-52. (d) Corrigan, C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr. Opin. Invest. Drugs (PharmaPress Ltd.) 2000, 1, 321-328. (e) Saunders, J.; Tarby, C. M. Drug Discovery Today 1999, 4, 80-92. (f) Kay, A. B.; Corrigan, C. J. Asthma. Eosinophils and neutrophils. Br. Med. Bull. 1992, 48, 51-64. (g) Bousquet, J.; Chanez, P.; Lacoste, J. Y.; Barneon, G.; Ghavanian, N.; Enander, I.; Venge, P.; Ahlstedt, S.; Simony-Lafontaine, J.; Godard, P.; Michel, F.-B. Eosinophilic inflammation in asthma. N. Engl. J. Med. 1990, 323, 1033-1039. (h) Minshall, E. M.; Cameron, L.; Lavigne, F.; Leung, D. Y.; Hamilos, D.; Garcia-Zepada, E. A.; Rothenberg, M.; Luster, A. D.; Hamid, Q. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am. J. Respir. Cell Mol. Biol. 1997, 17, 683-690. (i) Daugherty, B. L.; Siciliano, S. J.; DeMartino, J. A.; Malkowitz, L.; Sirotina, A.; Springer, M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med. 1996, 183, 2349-2354. (j) Carter, P. H. Chemokines receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr. Opin. Chem. Biol. 2002, 6, 510-525.
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