2. Academic Validation
  3. Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia

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

Affiliation

  • 1 Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. izzat_raheem@merck.com
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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