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Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Aug 01; Vol. 27 (15), pp. 3440-3450. Date of Electronic Publication: 2019 Jun 19. - Publication Year :
- 2019
-
Abstract
- We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cattle
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Phosphodiesterase Inhibitors chemical synthesis
Phosphodiesterase Inhibitors chemistry
Pyrimidines chemical synthesis
Pyrimidines chemistry
Stilbenes chemistry
Structure-Activity Relationship
Drug Discovery
Phosphodiesterase Inhibitors pharmacology
Phosphoric Diester Hydrolases metabolism
Pyrimidines pharmacology
Stilbenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 27
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31235264
- Full Text :
- https://doi.org/10.1016/j.bmc.2019.06.021