Design, synthesis, and progress toward optimization of potent small molecule antagonists of CC chemokine receptor 8 (CCR8).
Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.
Ghosh
Shomir
S
Department of Medicinal Chemistry, Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. sghosh@mpi.com
Elder
Amy
A
Guo
Jianping
J
Mani
Ukti
U
Patane
Michael
M
Carson
Kenneth
K
Ye
Qing
Q
Bennett
Robert
R
Chi
Shannon
S
Jenkins
Tracy
T
Guan
Bing
B
Kolbeck
Roland
R
Smith
Sean
S
Zhang
Cheng
C
LaRosa
Gregory
G
Jaffee
Bruce
B
Yang
Hua
H
Eddy
Priya
P
Lu
Chuang
C
Uttamsingh
Vinita
V
Horlick
Robert
R
Harriman
Geraldine
G
Flynn
Daniel
D
D000586:Amination; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D015195:Drug Design; D004986:Ether / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C103330:CCR8 protein, human; D010880:Piperidines; D011759:Pyrrolidines; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D004986:Ether