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

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• 作者：Izzat T. Raheem ; Michael J. Breslin ; Christine F ; ozzi ; Joy Fuerst ; Nicole Hill ; Sarah Huszar ; Monika K ; ebo ; 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
• 关键词：Phosphodiesterase 10A inhibitor ; Schizophrenia ; Hyperlocomotion assay ; Conditioned avoidance response assay ; Tetrahydropyridopyrimidine
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 September, 2012
• 年：2012
• 卷：22
• 期：18
• 页码：5903-5908
• 全文大小：797 K

文摘

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 m>in vivom> 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.