Identification of Potent, Selective Non-peptide CC Chemokine Receptor-3 Antagonist That Inhibits Eotaxin-, Eotaxin-2-, and Monocyte Chemotactic Protein-4-induced Eosinophil Migration

Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating p...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-11, Vol.275 (47), p.36626-36631
Main Authors: White, John R., Lee, Judithann M., Dede, Kimberly, Imburgia, Christina S., Jurewicz, Anthony J., Chan, George, Fornwald, James A., Dhanak, Dashyant, Christmann, Lisa T., Darcy, Michael G., Widdowson, Katherine L., Foley, James J., Schmidt, Dulcie B., Sarau, Henry M.
Format: Article
Language:English
Subjects:
Asthma - physiopathology
Benzamides - pharmacology
Binding, Competitive
Calcium - metabolism
CCR3 protein
Cell Line
Cell Movement - drug effects
Chemokine CCL11
Chemokine CCL24
Chemokines, CC - antagonists & inhibitors
Cytokines - antagonists & inhibitors
Eosinophils - drug effects
eotaxin
Humans
Monocyte Chemoattractant Proteins - antagonists & inhibitors
monocyte chemotactic protein 3
Naphthalenes - pharmacology
Phenylalanine - analogs & derivatives
Phenylalanine - pharmacology
RANTES
Receptors, CCR3
Receptors, Chemokine - antagonists & inhibitors
Receptors, Chemokine - physiology
Receptors, HIV - antagonists & inhibitors
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Summary:Eosinophils have been implicated in the pathogenesis of asthma and other allergic diseases. Several CC chemokines including eotaxin (CCL-11), eotaxin-2 (CCL-24), RANTES (CCL-5), and monocyte chemotactic protein-3 (MCP-3, CCL-7) and 4 (MCP-4, CCL-13) are potent eosinophil chemotactic and activating peptides acting through CC chemokine receptor-3 (CCR3). Thus, antagonism of CCR3 could have a therapeutic role in asthma and other eosinophil-mediated diseases. A high throughput, cellular functional screen was configured using RBL-2H3 cells stably expressing CCR3 (RBL-2H3-CCR3) to identify non-peptide receptor antagonists. A small molecule CCR3 antagonist was identified, SK&F 45523, and chemical optimization led to the generation of a number of highly potent, selective CCR3 antagonists including SB-297006 and SB-328437. These compounds were further characterized in vitro and demonstrated high affinity, competitive inhibition of125I-eotaxin and 125I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca2+ mobilization in RBL-2H3-CCR3 cells and eosinophils. Additionally, SB-328437 inhibited eosinophil chemotaxis induced by three ligands that activate CCR3 with similar potencies. Selectivity was affirmed using a panel of 10 seven-transmembrane receptors. This is the first description of a non-peptide CCR3 antagonist, which should be useful in further elucidating the pathophysiological role of CCR3 in allergic inflammatory diseases.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M006613200