title: Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.
abstract: Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
authors.affiliation: Bristol-Myers Squibb Company, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. george.delucca@bms.com
authors.forename: George V
authors.initials: GV
authors.lastname: De Lucca
authors.forename: Ui Tae
authors.initials: UT
authors.lastname: Kim
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Vargo
authors.forename: John V
authors.initials: JV
authors.lastname: Duncia
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Santella
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Gardner
authors.forename: Changsheng
authors.initials: C
authors.lastname: Zheng
authors.forename: Ann
authors.initials: A
authors.lastname: Liauw
authors.forename: Zhang
authors.initials: Z
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Emmett
authors.forename: Dean A
authors.initials: DA
authors.lastname: Wacker
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Welch
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Stowell
authors.forename: Eric A
authors.initials: EA
authors.lastname: Wadman
authors.forename: Anuk M
authors.initials: AM
authors.lastname: Das
authors.forename: Paul
authors.initials: P
authors.lastname: Davies
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Graden
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; D001682:Biological Availability; D016466:CHO Cells; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010539:Permeability; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C500084:1-(2-((3-(4-fluorobenzyl)piperidin-1-yl)methyl)cyclohexyl)-3-(3-acetylphenyl)urea; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D003510:Cyclohexanes; D010671:Phenylurea Compounds; D010880:Piperidines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D014508:Urea; D002118:Calcium