Fused bicyclic pyrrolizinones as new scaffolds for human NK₁ antagonists

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• 作者：Gregori J. Morriello ; Robert J. DeVita ; S ; er G. Mills ; Jonathan R. Young ; Peter Lin ; George Doss ; Gary G. Chicchi ; Julie DeMartino ; Marc M. Kurtz ; Kwei-Lan C. Tsao ; Emma Carlson ; Karen Townson ; Alan W
• 关键词：Avocado ; Lenticel damage ; Measles ; Colletotrichum acutatum ; Phomopsis
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 出版时间：1 March 2008
• 年：2008
• 卷：16
• 期：5
• 页码：2156-2170
• 全文大小：276 K

文摘

Previous work on human NK₁ antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.