Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Izzat T Raheem, Michael J Breslin, Christine Fandozzi, Joy Fuerst, Nicole Hill, Sarah Huszar, Monika Kandebo, Somang H Kim, Bennett Ma, Georgia McGaughey, John J Renger, John D Schreier, Sujata Sharma, Sean Smith, Jason Uslaner, Youwei Yan, Paul J Coleman, Christopher D Cox
Bioorganic & Medicinal Chemistry Letters 2012 September 15, 22 (18): 5903-8
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.

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