Conformational analysis of N,N

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• 作者：Christopher D. Cox ; Georgia B. McGaughey ; Michael J. Bogusky ; David B. Whitman ; Richard G. Ball ; Christopher J. Winrow ; John J. Renger ; Paul J. Coleman
• 关键词：Orexin receptor antagonist ; Diazepane ; Pi-stacking ; Macrocyclicization
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：1 June 2009
• 年：2009
• 卷：19
• 期：11
• 页码：2997-3001
• 全文大小：533 K

文摘

NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular π-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation.