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

@article{Raheem2012DiscoveryOT,
  title={Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.},
  author={Izzat T. Raheem and Michael J. Breslin and Christine M Fandozzi and Joy Fuerst and Nicole Hill and Sarah L. Huszar and Monika Kandebo and Somang Hope Kim and Bennett K Ma and Georgia B. McGaughey and John Renger and John D. Schreier and Sujata Pandit Sharma and Sean M. Smith and Jason M. Uslaner and Youwei Yan and Paul J. Coleman and Christopher D. Cox},
  journal={Bioorganic & medicinal chemistry letters},
  year={2012},
  volume={22 18},
  pages={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… CONTINUE READING
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