Benzimidazoles as Potent and Orally Active mGlu5 Receptor Antagonists with an Improved PK Profile

A focused chemical optimization effort of compound 1 based on metabolite elucidation is described, resulting in 15i, a highly potent and selective mGlu5 receptor antagonist with an improved pharmacokinetic profile compared to 1. Characterization of 15i in vivo in the fear-potentiated startle (FPS) p...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2011-01, Vol.2 (1), p.58-62
Main Authors: Carcache, David, Vranesic, Ivo, Blanz, Joachim, Desrayaud, Sandrine, Fendt, Markus, Glatthar, Ralf
Format: Article
Language:English
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Letter
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Summary:A focused chemical optimization effort of compound 1 based on metabolite elucidation is described, resulting in 15i, a highly potent and selective mGlu5 receptor antagonist with an improved pharmacokinetic profile compared to 1. Characterization of 15i in vivo in the fear-potentiated startle (FPS) paradigm revealed a robust reduction of conditioned fear behavior. This effect nicely correlates with the rat brain pharmacokinetics.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml100215b