Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.

Graphical abstractNovel mGluR5 antagonists have been developed. SAR studies and lead optimizations are described, which result in compound 16m with high efficacy in animal models.Figure optionsDownload full-size imageDownload as PowerPoint slide