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

被引：9

作者：

Carcache, David ^{[1
]}

Vranesic, Ivo ^{[1
]}

Blanz, Joachim ^{[1
]}

Desrayaud, Sandrine ^{[1
]}

Fendt, Markus ^{[1
]}

Glatthar, Ralf ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2011年 / 2卷 / 01期

关键词：

mGlu5; benzimidazoles; pharmacokinetics; METABOTROPIC GLUTAMATE-RECEPTOR; PHARMACOLOGY; ANXIETY; TARGETS;

D O I：

10.1021/ml100215b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A focused chemical optimization effort of a 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.

引用

页码：58 / 62

页数：5

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