Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators
Journal of Medicinal Chemistry2012Vol. 55(21), pp. 9089–9106
Citations Over TimeTop 10% of 2012 papers
François Bischoff, Didier Berthelot, Michel De Cleyn, Gregor J. Macdonald, Garrett Minne, Daniel Oehlrich, Serge Pieters, Michel Surkyn, Andrés A. Trabanco, Gary Tresadern, Sven Van Brandt, Ingrid Velter, Mirko Zaja, Herman Borghys, Chantal Masungi, Marc Mercken, Harrie J. M. Gijsen
Abstract
The design and the synthesis of several chemical subclasses of imidazole containing γ-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 γ-secretase modulatory profile by lowering Aβ42 and Aβ40 levels combined with an especially pronounced increase in Aβ38 and Aβ37 levels while leaving the total levels of amyloid peptides unchanged.
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