|
ИСТИНА |
Войти в систему Регистрация |
ИПМех РАН |
||
Design and Characterization of Novel Small Molecule Activators of Excitatory Amino Acid Transporter 2статья Исследовательская статья
- Авторы: Sanjay Das, Trubnikov Artem V., Novoselov Anton M., Kurkin Alexander V., Beld Joris, Altieri Andrea, Kortagere Sandhya
- Журнал: ACS Medicinal Chemistry Letters
- Год издания: 2022
- Издательство: American Chemical Society
- Местоположение издательства: United States
- DOI: 10.1021/acsmedchemlett.2c00304
- Аннотация: Excitotoxicity in the brain is a causal factor in several neurological and neurodegenerative disorders. Excitatory amino acid transporter 2 (EAAT2), an astrocytic glutamate transporter involved in the clearance of >80% of synaptic glutamate, is considered a therapeutically relevant target for excitotoxicity. We have previously designed GT951, an activator of EAAT2 with nanomolar efficacy but limited in vivo bioavailability. In this study, a pharmacophore-based screening and optimization resulted in the design of GTS467 and GTS511. GTS467 and GTS511 have low nanomolar efficacy in the glutamate uptake assay. Pharmacokinetic profiles (PK) of GTS511 show a >6 h half-life and higher bioavailability in plasma and the brain under all three routes of administration in rats. Similarly, GTS467 has high oral bioavailability (80–85%) in the brain and plasma with a >1 h half-life under all three dosing routes. These encouraging efficacy and PK profiles suggest that GTS511 and GTS467 can be further developed to treat neurological disorders caused by excitotoxicity.
- Добавил в систему: Куркин Александр Витальевич