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Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Sep 15; Vol. 22 (18), pp. 5903-8. Date of Electronic Publication: 2012 Jul 27. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Cyclic GMP analysis
Dose-Response Relationship, Drug
Humans
Molecular Structure
Phosphodiesterase Inhibitors administration & dosage
Phosphodiesterase Inhibitors chemistry
Phosphoric Diester Hydrolases metabolism
Pyridines administration & dosage
Pyridines chemistry
Pyrimidines administration & dosage
Pyrimidines chemistry
Rats
Structure-Activity Relationship
Drug Discovery
Phosphodiesterase Inhibitors therapeutic use
Pyridines pharmacology
Pyrimidines pharmacology
Schizophrenia drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 22892116
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.07.072