Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu 2 ) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores.

A scaffold hopping exercise from a monocyclic mGlu(2) NAM with poor rodent PK led to two novel heterobicyclic series of mGlu(2) NAMs based on either a functionalized pyrazolo[1,5-a]pyrimidine-5-carboxamide core or a thieno[3,2-b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu(2) NAM potency, selectivity (versus mGlu(3) and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.