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Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Oct 08; Vol. 58 (19), pp. 7888-94. Date of Electronic Publication: 2015 Sep 25. - Publication Year :
- 2015
-
Abstract
- Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
- Subjects :
- Animals
Chemistry Techniques, Synthetic
Crystallography, X-Ray
Disease Models, Animal
Dizocilpine Maleate pharmacology
Drug Discovery
Drug Evaluation, Preclinical methods
Humans
Male
Phosphodiesterase Inhibitors chemical synthesis
Phosphoric Diester Hydrolases chemistry
Phosphoric Diester Hydrolases metabolism
Pyrimidines chemistry
Rats, Wistar
Schizophrenia drug therapy
Phosphodiesterase Inhibitors chemistry
Phosphodiesterase Inhibitors pharmacology
Structure-Activity Relationship
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26378882
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b00983