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

  • Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8. doi: 10.1016/j.bmcl.2012.07.072.
Izzat T Raheem  1 ,  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
Affiliations
  • 1. Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. [email protected]
PMID: 22892116 DOI: 10.1016/j.bmcl.2012.07.072
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.

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