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Design, Synthesis, and Progress toward Optimization of Potent Small Molecule Antagonists of CC Chemokine Receptor 8 (CCR8)

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journal contribution
posted on 04.05.2006, 00:00 by Shomir Ghosh, Amy Elder, Jianping Guo, Ukti Mani, Michael Patane, Kenneth Carson, Qing Ye, Robert Bennett, Shannon Chi, Tracy Jenkins, Bing Guan, Roland Kolbeck, Sean Smith, Cheng Zhang, Gregory LaRosa, Bruce Jaffee, Hua Yang, Priya Eddy, Chuang Lu, Vinita Uttamsingh, Robert Horlick, Geraldine Harriman, Daniel Flynn
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.