Modulation of excitatory glutamate neurotransmission through activation of the metabotropic glutamate receptor 2 (mGluR2) represents a promising approach for the treatment of positive symptoms associated with schizophrenia. Although the dual mGluR2/3 agonist LY2140023 has had mixed results in the clinic, positive allosteric modulators (PAMs) of mGluR2 may overcome the shortcomings of orthosteric agonists by achieving superior subtype selectivity and tuning physiological effects through promoting activation of receptors only in the presence of endogenous ligand. Herein we describe the optimization of an HTS hit benzisoxazole 1  to aza-benzimidazolone 2  through truncation and identification of the key pharmacophore, followed by core modification to improve physico-chemical properties. Following oral administration, compound 2  was identified as an efficacious mGluR2 PAM in pre-clinical measures of antipsychotic-like effects at CSF exposures consistent with in vitro potency. In order to improve in vivo potency, compound 2  was further optimized with a focus on potency, physico-chemical properties and pharmacokinetics to provide benzothiadiazole-dione 3  as an orally bioavailable mGluR2 PAM. The in-depth characterization of compound 3 will be presented, including the PK/PD relationship between plasma concentrations, receptor occupancy, efficacy in rodent behavioral tests, as well as the attenuation of MK-801-induced glutamate release in the medial prefrontal cortex.

Development of benzothiadiazole-diones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.