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

Novel mGluR5 antagonists have been developed. SAR studies and lead optimizations are described, which result in compound 16m with high efficacy in animal models. 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.