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

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 18; pp. 5903 - 5908
• Main Authors: Raheem, Izzat T., Breslin, Michael J., Fandozzi, Christine, Fuerst, Joy, Hill, Nicole, Huszar, Sarah, Kandebo, Monika, Kim, Somang H., Ma, Bennett, McGaughey, Georgia, Renger, John J., Schreier, John D., Sharma, Sujata, Smith, Sean, Uslaner, Jason, Yan, Youwei, Coleman, Paul J., Cox, Christopher D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-09-2012; Elsevier
• Subjects: Administration, Oral; Animals; antipsychotics; Biological and medical sciences; chemistry; Conditioned avoidance response assay; cyclic GMP; Cyclic GMP - analysis; Dose-Response Relationship, Drug; Drug Discovery; haloperidol; Humans; Hyperlocomotion assay; Medical sciences; Molecular Structure; pharmacokinetics; Pharmacology. Drug treatments; Phosphodiesterase 10A inhibitor; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - therapeutic use; Phosphoric Diester Hydrolases - metabolism; prolactin; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Schizophrenia; Schizophrenia - drug therapy; secretion; Structure-Activity Relationship; Tetrahydropyridopyrimidine; weight gain; Schizophrenia; Hyperlocomotion assay; Tetrahydropyridopyrimidine; Phosphodiesterase 10A inhibitor; Conditioned avoidance response assay; Enzyme; Psychotropic; Enzyme inhibitor; Esterases; Phosphoric diester hydrolases; Psychosis; Phosphodiesterase inhibitor; Hydrolases; Antipsychotic
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.072

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.