Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator

Glutamate plays a key role in cognition and mood, andit has beenshown that inhibiting ionotropic glutamate receptors disrupts cognition,while enhancing ionotropic receptor activity is pro-cognitive. Oneapproach to elevating glutamatergic tone has been to antagonize presynapticmetabotropic glutamate receptor 2 (mGluR2). A desire for selectivityover the largely homologous mGluR3 motivated a strategy to achieveselectivity through the identification of mGluR2 negative allostericmodulators (NAMs). Extensive screening and optimization efforts ledto the identification of a novel series of 4-arylquinoline-2-carboxamides.This series was optimized for mGluR2 NAM potency, clean off-targetactivity, and desirable physical properties, which resulted in theidentification of improved C4 and C7 substituents. The initial leadcompound from this series was Ames-positive in a single strain withmetabolic activation, indicating that a reactive metabolite was likelyresponsible for the genetic toxicity. Metabolic profiling and Amesassessment across multiple analogs identified key structure-activityrelationships associated with Ames positivity. Further optimizationled to the Ames-negative mGluR2 negative allosteric modulator MK-8768.