Discovery of 6,7-Dihydropyrazolo[1,5- a]pyrazin-4(5 H)-one Derivatives as mGluR2 Negative Allosteric Modulators with In Vivo Activity in a Rodent's Model of Cognition

Abstract

Allosteric modulators of the metabotropic group II receptors, mGluR₂ and mGluR₃, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR₂ negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR₂ NAM potency and subsequent selection of compound 11 based on its overall profile, including selectivity and ADMET properties. Further pharmacokinetic-pharmacodynamic (PK-PD) relationship built showed that compound 11 occupied the mGluR₂ receptor in a dose-dependent manner. Additionally, the compound revealed in vivo activity in V-maze as a model of cognition from a dose of 0.32 mg/kg. Compound 11 was selected to be evaluated further.