Arylmethoxypyridines as novel, potent and orally active mGlu5 receptor antagonists

Optimisation of affinity, chemical stability, metabolic stability and solubility led from a chemically labile HTS hit 1 to mGlu5 receptor antagonists (24–26) with high affinity for the allosteric MPEP binding site, improved microsomal metabolic stability and anxiolytic-like activity in vivo as assessed by the Vogel conflict drinking test.

Graphical abstractThe optimisation of a chemically unstable HTS hit led to mGluR5 antagonists with high affinity for the allosteric MPEP binding site and anxiolytic-like activity in vivo.Figure optionsDownload full-size imageDownload as PowerPoint slide