Schizophrenia is a chronic and debilitating neurological disease with onset typically occurring during early adulthood.  The disease is characterized by a combination of positive (hallucinations), negative (anhedonia, social withdrawal), and cognitive symptoms, and is estimated to affect 1% of the global population.  While currently marketed 'typical' and 'atypical' therapeutics exist, they are prone to an array of adverse events (AEs), often resulting in discontinuation due to poor efficacy and/or tolerability.  As such, alternative pharmacological approaches toward treating schizophrenia represent an unmet medical need.              The phosphodiestereases (PDEs) are a superfamily of 11 enzymes responsible for the hydrolytic degradation of the second messengers cAMP and cGMP.  Specifically, PDE10 is highly expressed and localized in the mammalian striatum, and is implicated in the regulation of cyclic nucleotide signalling cascades that intersect both the glutamatergic and dopaminergic pathways regulating behavioral control.  As such, inhibition of PDE10 is hypothesized to represent a mechanistically novel approach toward the treatment of schizophrenia, and recent preclinical results support this hypothesis.                          We describe the discovery and development of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of PDE10 obtained by systematic optimization of a proprietary Merck HTS lead.  Leading compounds exhibit sub-nanomolar potencies, excellent pharmacokinetic (PK) properties, and clean off-target profiles.  These inhibitors display in vivo target engagement as measured by both an ex vivo occupancy assay and increased striatal cGMP levels upon oral dosing.  They also display dose-dependent efficacy in key pharmacodynamic (PD) assays predictive of anti-psychotic activity, including the psychostimulant-induced rat hyperlocomotion assay and the conditioned avoidance response assay.

Discovery of phosphodiesterase-10 (PDE10) inhibitors for the treatment of schizophrenia

242nd National Meeting (2011)

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