Preclinical evaluation of MK-8189: A novel phosphodiesterase 10A inhibitor for the treatment of schizophrenia.

Abstract

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits subnanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cyclic guanosine monophosphate and phospho glutamate receptor 1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P and enkephalin after MK-8189 administration. The PDE10A tracer [³H]MK-8193 was used to determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat-conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ∼48%. MK-8189 significantly reversed an MK-801-induced deficit in prepulse inhibition at PDE10A EO of ∼47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [¹¹C]MK-8193 in positron emission tomography studies, and plasma concentrations of 127 nM MK-8189 yielded ∼50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ∼29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. SIGNIFICANCE STATEMENT: We describe the primary pharmacology of MK-8189, a phosphodiesterase 10A (PDE10A) inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients.