Discovery of a Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitor for the Potential Treatment of Schizophrenia

Abstract

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation

“…Since D 1 dopamine receptors are positively connected to cAMP and D 2 dopamine receptors are negatively connected to cAMP, inhibitors of PDE10A are currently being developed and tested as antipsychotic medication (Bartolomé-Nebreda et al, 2014). The linkage analysis identifies two homozygous carriers who inherited the haplotype from both parents who were first cousins.…”

Guidelines for the successful generation of protein–ligand complex crystals

“…For the example shown, a data set could be collected and the structure solved without significant loss in resolution or map quality compared with nonsoaked apo crystals. Bartolomé -Nebreda et al, 2014), for which the most likely explanation is steric restriction. One is rarely as lucky as in the case of PDE10A, where the ligand-binding mode near a packing interface can be checked against an unaffected ligandbinding site within the same crystal.…”

Emerging drugs for schizophrenia: an update

“…PF-2545920 (MP-10) failed to show efficacy as a monotherapy in patients with acute exacerbation of schizophrenia [108]. After terminating a placebo-controlled Phase II trial of the PDE-10a inhibitor PF-2545920 (MP-10) in February 2008, Pfizer is currently testing PF-2545920 in the adjunctive treatment of out-patients with sub-optimally controlled symptoms of schizophrenia [109].…”