Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent 纬-Secretase Modulators

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• 作者：Francois Bischoff ; Didier Berthelot ; Michel De Cleyn ; Gregor Macdonald ; Garrett Minne ; Daniel Oehlrich ; Serge Pieters ; Michel Surkyn ; Andr茅s A. Trabanco ; Gary Tresadern ; Sven Van Brandt ; Ingrid Velter ; Mirko Zaja ; Herman Borghys ; Chantal Masungi ; Marc Mercken ; Harrie J. M. Gijsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9089-9106
• 全文大小：638K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

The design and the synthesis of several chemical subclasses of imidazole containing 纬-secretase modulators (GSMs) is described. Conformational restriction of pyridone 4 into bicyclic pyridone isosteres has led to compounds with high in vitro and in vivo potency. This has resulted in the identification of benzimidazole 44a as a GSM with low nanomolar potency in vitro. In mouse, rat, and dog, this compound displayed the typical 纬-secretase modulatory profile by lowering A尾42 and A尾40 levels combined with an especially pronounced increase in A尾38 and A尾37 levels while leaving the total levels of amyloid peptides unchanged.