title: Benzimidazoles as Potent and Orally Active mGlu5 Receptor Antagonists with an Improved PK Profile.
abstract: 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.
authors.affiliation: Global Discovery Chemistry.
authors.forename: David
authors.initials: D
authors.lastname: Carcache
authors.affiliation: Neuroscience.
authors.forename: Ivo
authors.initials: I
authors.lastname: Vranesic
authors.affiliation: Global Discovery Chemistry.
authors.forename: Joachim
authors.initials: J
authors.lastname: Blanz
authors.affiliation: Global Discovery Chemistry.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.affiliation: Neuroscience.
authors.forename: Markus
authors.initials: M
authors.lastname: Fendt
authors.affiliation: Global Discovery Chemistry.
authors.forename: Ralf
authors.initials: R
authors.lastname: Glatthar
keywords: benzimidazoles; mGlu5; pharmacokinetics