title: Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists.
abstract: The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08542-5400, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Gardner
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Santella
authors.forename: John V
authors.initials: JV
authors.lastname: Duncia
authors.forename: Melissa
authors.initials: M
authors.lastname: Estrella
authors.forename: Paul S
authors.initials: PS
authors.lastname: Watson
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Clark
authors.forename: Soo S
authors.initials: SS
authors.lastname: Ko
authors.forename: Patricia
authors.initials: P
authors.lastname: Welch
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Nicole
authors.initials: N
authors.lastname: Stowell
authors.forename: Eric
authors.initials: E
authors.lastname: Wadman
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.forename: Kimberley
authors.initials: K
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: Dean A
authors.initials: DA
authors.lastname: Wacker
mesh_terms: D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; C017680:propylurea; D014508:Urea