Identification and characterization of novel antagonists of the CCR3 receptor.
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.
Warrior
Usha
U
Abbott Laboratories, Global Pharmaceutical Products Division, Abbott Park, IL, USA. Usha.Warrior@abbott.com
McKeegan
Evelyn M
EM
Rottinghaus
Susan M
SM
Garcia
Lora
L
Traphagen
Linda
L
Grayson
George
G
Komater
Victoria
V
McNally
Teresa
T
Helfrich
Rosalind
R
Harris
Richard R
RR
Bell
Randy L
RL
Burns
David J
DJ
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
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