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Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Feb 01; Vol. 29 (3), pp. 406-412. Date of Electronic Publication: 2018 Dec 19. - Publication Year :
- 2019
-
Abstract
- Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Dose-Response Relationship, Drug
Heterocyclic Compounds, 2-Ring chemical synthesis
Heterocyclic Compounds, 2-Ring chemistry
Humans
Models, Molecular
Molecular Structure
Phosphodiesterase Inhibitors chemical synthesis
Phosphodiesterase Inhibitors chemistry
Pyrazines chemical synthesis
Pyrazines chemistry
Rats
Structure-Activity Relationship
Thiazoles chemical synthesis
Thiazoles chemistry
Heterocyclic Compounds, 2-Ring pharmacology
Phosphodiesterase Inhibitors pharmacology
Phosphoric Diester Hydrolases metabolism
Pyrazines pharmacology
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 30587449
- Full Text :
- https://doi.org/10.1016/j.bmcl.2018.12.029