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Identification of Potent, Selective Non-Peptide CC Chemokine receptor-3 Antagonist That Inhibits Eotaxin-, eotaxin-2-, and Monocyte Chemotactic protein-4-induced Eosinophil Migration

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 R White, J M Lee, K Dede, C S Imburgia, A J Jurewicz, G Chan, J A Fornwald, D Dhanak, L T Christmann, M G Darcy, K L Widdowson, J J Foley, D B Schmidt, H M Sarau

J Biol Chem. 2000 Nov 24;275(47):36626-31.

PMID: 10969084

Abstract:

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 of (125)I-eotaxin and (125)I-MCP-4 binding to human eosinophils. The compounds were potent inhibitors of eotaxin- and MCP-4-induced Ca(2+) 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP58816696	SB 297006		58816-69-6	Price

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