Lead optimization of 4,4-biaryl piperidine amides as 纬-secretase inhibitors

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• 作者：Joshua Close^a ; ^{joshua_close@merck.com} ; Richard Heidebrecht Jr.^a ; John Hendrix^a ; Chaomin Li^a ; Ben Munoz^a ; Laura Surdi^a ; Solomon Kattar^a ; Paul Tempest^a ; Paul Moses^a ; Xiaoliu Geng^a ; Bethany Hughes^a ; Nadya Smotrov^a ; Chris Moxham^a ; Jennifer Chapnick^a ; Ilona Kariv^a ; George Nikov^a ; Julie Elizabeth Burke^a ; Sujal Deshmukh^a ; Valentina Jeliazkova-Mecheva^a ; John Kevin Leach^a ; Damaris Diaz^a ; Lin Xu^a ; Ziping Yang^a ; Gloria Kwei^a ; Lily Moy^a ; Sanjiv Shah^a ; Flobert Tanga^a ; Candia Kenefic^a ; Dan Savage^a ; Mark Shearman^a ; Richard G. Ball^b ; Michael J. McNevin^b ; Amanda Markarewicz^b ; Thomas Miller^a
• 关键词：Alzheimer&rsquo ; s disease ; 纬-Secretase ; A尾42 ; APP-YAC ; In vivo clearance
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May, 2012
• 卷：22
• 期：9
• 页码：3203-3207
• 文件大小：375 K

摘要

Alzheimer鈥檚 disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of 尾-amyloid. 纬-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of 尾-amyloid peptides; one of which, A尾42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine 纬-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral A尾42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of 纬-secretase inhibitors capable of lowering cerebral A尾42 production in mice.