The discovery of potent, selective, and orally bioavailable hNK₁ antagonists derived from pyrrolidine

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• 作者：Peter Lin ; Lehua Chang ; Robert J. DeVita ; Jonathan R. Young ; Ronsar Eid ; Xinchun Tong ; Song Zheng ; Richard G. Ball ; Nancy N. Tsou ; Gary G. Chicchi ; Marc M. Kurtz ; Kwei-Lan C. Tsao ; Alan Wheeldon ; Emma
• 关键词：NK₁ ; Neurokinin NK₁ antagonist ; Tachykinin NK₁ antagonist ; Substance P antagonist
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 September 2007
• 卷：17
• 期：18
• 页码：5191-5198
• 文件大小：424 K

摘要

SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK₁ antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ₉₀ <img src="http://www.sciencedirect.com/scidirimg/entities/223c.gif" alt="not, vert, similar" border=0> 300 ng/ml.