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Discovery and Characterization of a Novel Dihydroisoxazole Class of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Potentiators
- Source :
- Journal of Medicinal Chemistry. 56:9180-9191
- Publication Year :
- 2013
- Publisher :
- American Chemical Society (ACS), 2013.
-
Abstract
- Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.
- Subjects :
- Male
Models, Molecular
Stereochemistry
Allosteric regulation
AMPA receptor
Absorption
Mice
Structure-Activity Relationship
Allosteric Regulation
Drug Discovery
Animals
Humans
Structure–activity relationship
Receptors, AMPA
Receptor
ADME
Drug discovery
Chemistry
Isoxazoles
Potentiator
Ligand (biochemistry)
High-Throughput Screening Assays
Protein Structure, Tertiary
Rats
nervous system
Biochemistry
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804, 00222623, and 04725379
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....c56e4065349b607cc298e139b742e784