Tetrahydroindolizinone NK₁ antagonists

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• 作者：Jianming Bao ; Huagang Lu ; Gregori J. Morriello ; Emma J. Carlson ; Alan Wheeldon ; Gary G. Chicchi ; Marc M. Kurtz ; Kwei-Lan C. Tsao ; Song Zheng ; Xinchun Tong ; S ; er G. Mills ; Robert J. DeVita
• 关键词：Tetrahydroindolizinone ; NK1 ; Antagonists ; Gerbil foot tapping ; IP1
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 April 2010
• 年：2010
• 卷：20
• 期：7
• 页码：2354-2358
• 全文大小：753 K

文摘

A new class of potent NK₁ receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK₁ receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK₁ binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P₄₅₀ inhibition and hPXR induction profiles.