Substituted fused bicyclic pyrrolizinones as potent, orally bioavailable hNK₁ antagonists

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• 作者：Gregori J. Morriello ; S ; er G. Mills ; Tricia Johnson ; Mikhail Reibarkh ; Gary Chicchi ; Julie DeMartino ; Marc Kurtz ; P. Davies ; K.L.C. Tsao ; Song Zheng ; Xinchun Tong ; Emma Carlson ; Karen Townson ; F.D. Ta
• 关键词：Neurokinin-1 antagonist ; Nuerokinin receptor ; Substance P
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：15 March 2010
• 年：2010
• 卷：20
• 期：6
• 页码：2007-2012
• 全文大小：1387 K

文摘

Previous work on human NK₁ (hNK₁) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural–activity-relationship studies on simple α- and β-substituted compounds of this series provided several potent and bioavailable hNK₁ antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100 % inhibition of the foot-tapping response at 0.1 and 24 h with ID₅₀’s of less than 1 mpk. One particular α-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.