title: Discovery and structure-activity relationship of N-(ureidoalkyl)-benzyl-piperidines as potent small molecule CC chemokine receptor-3 (CCR3) antagonists.
abstract: Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.
authors.affiliation: Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0336, USA. george.delucca@bms.com
authors.forename: George V
authors.initials: GV
authors.lastname: De Lucca
authors.forename: Ui T
authors.initials: UT
authors.lastname: Kim
authors.forename: Curt
authors.initials: C
authors.lastname: Johnson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Vargo
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Welch
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Solomon
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: Soo S
authors.initials: SS
authors.lastname: Ko
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018926:Anti-Allergic Agents; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D014508:Urea; D002118:Calcium