Design, synthesis, and progress toward optimization of potent small molecule antagonists of CC chemokine receptor 8
Shomir Ghosh1, Amy Elder, Jianping Guo
1Department of Medicinal Chemistry, Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. sghosh@mpi.com
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.
