Discovery of Disubstituted Cyclohexanes as a New Class of CC Chemokine Receptor 2 Antagonists

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• 作者：Robert J. Cherney ; Ruowei Mo ; Dayton T. Meyer ; David J. Nelson ; Yvonne C. Lo ; Gengjie Yang ; Peggy A. Scherle ; Sandhya Mandlekar ; Zelda R. Wasserman ; Heather Jezak ; Kimberly A. Solomon ; Andrew J. Tebbe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 28, 2008
• 年：2008
• 卷：51
• 期：4
• 页码：721 - 724
• 全文大小：109K
• 年卷期：v.51,no.4(February 28, 2008)
• ISSN：1520-4804

文摘

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC₅₀ = 5.1 nM) and potent functional antagonism (calcium flux IC₅₀ = 18 nM and chemotaxis IC₅₀ = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.