title: Design, synthesis, and progress toward optimization of potent small molecule antagonists of CC chemokine receptor 8 (CCR8).
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. sghosh@mpi.com
authors.forename: Shomir
authors.initials: S
authors.lastname: Ghosh
authors.forename: Amy
authors.initials: A
authors.lastname: Elder
authors.forename: Jianping
authors.initials: J
authors.lastname: Guo
authors.forename: Ukti
authors.initials: U
authors.lastname: Mani
authors.forename: Michael
authors.initials: M
authors.lastname: Patane
authors.forename: Kenneth
authors.initials: K
authors.lastname: Carson
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Robert
authors.initials: R
authors.lastname: Bennett
authors.forename: Shannon
authors.initials: S
authors.lastname: Chi
authors.forename: Tracy
authors.initials: T
authors.lastname: Jenkins
authors.forename: Bing
authors.initials: B
authors.lastname: Guan
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.forename: Sean
authors.initials: S
authors.lastname: Smith
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Gregory
authors.initials: G
authors.lastname: LaRosa
authors.forename: Bruce
authors.initials: B
authors.lastname: Jaffee
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Priya
authors.initials: P
authors.lastname: Eddy
authors.forename: Chuang
authors.initials: C
authors.lastname: Lu
authors.forename: Vinita
authors.initials: V
authors.lastname: Uttamsingh
authors.forename: Robert
authors.initials: R
authors.lastname: Horlick
authors.forename: Geraldine
authors.initials: G
authors.lastname: Harriman
authors.forename: Daniel
authors.initials: D
authors.lastname: Flynn
mesh_terms: 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
chemical_list: C103330:CCR8 protein, human; D010880:Piperidines; D011759:Pyrrolidines; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D004986:Ether