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

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

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

Abstract
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.

PMID: 22892116 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001