title: Identification and characterization of novel antagonists of the CCR3 receptor.
abstract: Eotaxin, an inducer of eosinophil migration and activation, exerts its activity by binding to CCR3, the C-C chemokine receptor 3. An inhibitor of the eotaxin-CCR3 binding interaction may have potential as an anti-inflammatory drug for treatment of asthma, parasitic infections, and allergic disorders. A radioligand binding assay was developed using HEK cells transfected with CCR3, with (125)I eotaxin as the ligand. Whole cells grown on polylysine-coated plates were used as the receptor source for the screen. Screening of more than 200,000 compounds with this assay yielded a number of screening hits, and of these, 2 active novel antagonists were identified. These compounds showed inhibitory effects on eosinophil chemotaxis in both in vitro and in vivo assays.
authors.affiliation: Abbott Laboratories, Global Pharmaceutical Products Division, Abbott Park, IL, USA. Usha.Warrior@abbott.com
authors.forename: Usha
authors.initials: U
authors.lastname: Warrior
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
authors.forename: Susan M
authors.initials: SM
authors.lastname: Rottinghaus
authors.forename: Lora
authors.initials: L
authors.lastname: Garcia
authors.forename: Linda
authors.initials: L
authors.lastname: Traphagen
authors.forename: George
authors.initials: G
authors.lastname: Grayson
authors.forename: Victoria
authors.initials: V
authors.lastname: Komater
authors.forename: Teresa
authors.initials: T
authors.lastname: McNally
authors.forename: Rosalind
authors.initials: R
authors.lastname: Helfrich
authors.forename: Richard R
authors.initials: RR
authors.lastname: Harris
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
authors.forename: David J
authors.initials: DJ
authors.lastname: Burns
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000737:chemistry / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D011107:Polylysine / Q000737:chemistry; D011485:Protein Binding; D011869:Radioligand Assay; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000378:metabolism*; D014162:Transfection
chemical_list: C515456:CCL11 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018076:DNA, Complementary; D008024:Ligands; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D011107:Polylysine; D002118:Calcium