title: Small molecule antagonists of the CC chemokine receptor 4 (CCR4).
abstract: The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion.
authors: Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, MA 02139, USA. chengburdi@yahoo.com
authors: Douglas F
authors: DF
authors: Burdi
authors: Shannon
authors: S
authors: Chi
authors: Karen
authors: K
authors: Mattia
authors: Celeste
authors: C
authors: Harrington
authors: Zhan
authors: Z
authors: Shi
authors: Shaowu
authors: S
authors: Chen
authors: Swanee
authors: S
authors: Jacutin-Porte
authors: Robert
authors: R
authors: Bennett
authors: Kenneth
authors: K
authors: Carson
authors: Wei
authors: W
authors: Yin
authors: Vikram
authors: V
authors: Kansra
authors: Jose-Angel
authors: JA
authors: Gonzalo
authors: Anthony
authors: A
authors: Coyle
authors: Bruce
authors: B
authors: Jaffee
authors: Timothy
authors: T
authors: Ocain
authors: Marty
authors: M
authors: Hodge
authors: Gregory
authors: G
authors: LaRosa
authors: Geraldine
authors: G
authors: Harriman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C515355:Ccr4 protein, mouse; D009281:Naphthalenes; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D013449:Sulfonamides