Design and synthesis of novel CCR2 antagonists: Investigation of non-aryl/heteroaryl binding motifs

作者：Trujillo John I^*; Huang Wei; Hughes Robert O; Rogier D Joseph; Turner Steven R; Devraj Rajesh; Morton Philip A; Xue Chu Biao; Chao Ganfeng; Covington Maryanne B; Newton Robert C; Metcalf Brian

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(6): 1827-1831.

DOI：10.1016/j.bmcl.2011.01.052

• CCR2 antagonists
• MCP-1
• hERG
• Diazobicyclo[2.2.1]heptane
• Central penetrance
• Dofetilide
• Neuropathic pain
• Inflammatory diseases
• Fluoropyran

This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.

• 出版日期2011-3-15