Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone

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• 作者：Percy H. Carter ; ^{percy.carter@bms.com} ; Gregory D. Brown ; Sarah R. King ; Matthew E. Voss ; Andrew J. Tebben ; Robert J. Cherney ; Sandhya Mandlekar ; Yvonne C. Lo ; Gengjie Yang ; Persymphonie B. Miller ; Peggy A. Scherle ; Qihong Zhao ; Carl P. Decicco
• 关键词：Chemokine ; GPCR ; CCR2 ; Isostere
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May, 2012
• 卷：22
• 期：9
• 页码：3311-3316
• 文件大小：468 K

摘要

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of dFont">18, a compound that was suitable for studies in murine models of CCR2 activity.