Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

摘要: Abstract Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu 5 NAMs, we reasoned inactive nicotinamide could be modified through introduction fused heterocyclic core to generate potent NAMs. In this Letter, describe the synthesis and evaluation compounds demonstrate viability approach. Selected analogs were profiled variety vitro assays, two evaluated rat pharmacokinetic studies mouse model obsessive-compulsive disorder. Ancillary pharmacology screening revealed members exhibited moderate inhibition dopamine transporter (DAT), SAR developed expanded selectivity for versus DAT.