Novel sulfone-containing di- and trisubstituted cyclohexanes as potent CC chemokine receptor 2 (CCR2) antagonists

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• 作者：Robert J. Cherney ; Ruowei Mo ; Dayton T. Meyer ; Matthew E. Voss ; Yvonne C. Lo ; Gengjie Yang ; Persymphonie B. Miller ; Peggy A. Scherle ; Andrew J. Tebben ; Percy H. Carter ; Carl P. Decicco
• 关键词：CCR2 ; CCR2 antagonist ; Chemokine ; GPCR
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 July 2009
• 年：2009
• 卷：19
• 期：13
• 页码：3418-3422
• 全文大小：469 K

文摘

Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC₅₀ = 1.3 nM) and functional antagonism (calcium flux IC₅₀ = 0.5 nM and chemotaxis IC₅₀ = 0.2 nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.