title: Identification of potent, selective non-peptide CC chemokine receptor-3 antagonist that inhibits eotaxin-, eotaxin-2-, and monocyte chemotactic protein-4-induced eosinophil migration.
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.
authors.affiliation: Departments of Immunology, Biomolecular Discovery, Pulmonary Biology, Gene Expression Sciences, and Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. John_R_White@SBPHRD.COM
authors.forename: J R
authors.initials: JR
authors.lastname: White
authors.forename: J M
authors.initials: JM
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Dede
authors.forename: C S
authors.initials: CS
authors.lastname: Imburgia
authors.forename: A J
authors.initials: AJ
authors.lastname: Jurewicz
authors.forename: G
authors.initials: G
authors.lastname: Chan
authors.forename: J A
authors.initials: JA
authors.lastname: Fornwald
authors.forename: D
authors.initials: D
authors.lastname: Dhanak
authors.forename: L T
authors.initials: LT
authors.lastname: Christmann
authors.forename: M G
authors.initials: MG
authors.lastname: Darcy
authors.forename: K L
authors.initials: KL
authors.lastname: Widdowson
authors.forename: J J
authors.initials: JJ
authors.lastname: Foley
authors.forename: D B
authors.initials: DB
authors.lastname: Schmidt
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
mesh_terms: D001249:Asthma / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D019742:Chemokines, CC / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004804:Eosinophils / Q000187:drug effects*; D006801:Humans; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors*; D009281:Naphthalenes / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology; D015728:Receptors, HIV / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; C515456:CCL11 protein, human; C099677:CCL13 protein, human; C515484:CCL24 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D019742:Chemokines, CC; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D009281:Naphthalenes; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D015728:Receptors, HIV; C417502:SB 297006; C417503:SB 328437; C417504:SK&F 45523; D010649:Phenylalanine; D002118:Calcium