Small molecule antagonists of the CC chemokine receptor 4 (CCR4).
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.
Burdi
Douglas F
DF
Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, MA 02139, USA. chengburdi@yahoo.com
Chi
Shannon
S
Mattia
Karen
K
Harrington
Celeste
C
Shi
Zhan
Z
Chen
Shaowu
S
Jacutin-Porte
Swanee
S
Bennett
Robert
R
Carson
Kenneth
K
Yin
Wei
W
Kansra
Vikram
V
Gonzalo
Jose-Angel
JA
Coyle
Anthony
A
Jaffee
Bruce
B
Ocain
Timothy
T
Hodge
Marty
M
LaRosa
Gregory
G
Harriman
Geraldine
G
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*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C515355:Ccr4 protein, mouse; D009281:Naphthalenes; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D013449:Sulfonamides