Discovery of\n6,7-Dihydropyrazolo[1,5‑<i>a</i>]pyrazin-4(5<i>H</i>)‑one Derivatives\nas mGluR<sub>2</sub> Negative Allosteric Modulators with <i>In\nVivo</i> Activity in a Rodent’s Model of Cognition

Allosteric modulators of the metabotropic group II receptors,\nmGluR<sub>2</sub> and mGluR<sub>3</sub>, have been widely explored\ndue to their\nability to modulate cognitive and neurological functions in mood disorders,\nalthough none have been approved yet. In our search for new and selective\nmGluR<sub>2</sub> negative allosteric modulators (NAMs), series of\n6,7-dihydropyrazolo[1,5-<i>a</i>]pyrazin-4(5<i>H</i>)-one derivatives were identified from our published series of 1,3,5-trisubstituted\npyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement\nin the mGluR<sub>2</sub> NAM potency and subsequent selection of compound <b>11</b> based on its overall profile, including selectivity and\nADMET properties. Further pharmacokinetic-pharmacodynamic (PK–PD)\nrelationship built showed that compound <b>11</b> occupied the\nmGluR<sub>2</sub> receptor in a dose-dependent manner. Additionally,\nthe compound revealed <i>in vivo</i> activity in V-maze\nas a model of cognition from a dose of 0.32 mg/kg. Compound <b>11</b> was selected to be evaluated further.