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Journal article
Design and Characterization of Novel Small Molecule Activators of Excitatory Amino Acid Transporter 2
ACS medicinal chemistry letters, v 13(10), pp 1628-1633
13 Oct 2022
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- Design and Characterization of Novel Small Molecule Activators of Excitatory Amino Acid Transporter 2
- Creators
- Sanjay Das - Drexel UniversityArtem V. Trubnikov - Edasa Scientific Srls, Via Stingi 37, San Salvo (CH) 66050, ItalyAnton M. Novoselov - Edasa Scientific Srls, Via Stingi 37, San Salvo (CH) 66050, ItalyAlexander V. Kurkin - Edasa Scientific Srls, Via Stingi 37, San Salvo (CH) 66050, ItalyJoris Beld - Drexel UniversityAndrea Altieri - Edasa Scientific Srls, Via Stingi 37, San Salvo (CH) 66050, ItalySandhya Kortagere - Drexel University
- Publication Details
- ACS medicinal chemistry letters, v 13(10), pp 1628-1633
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000861611300001
- Scopus ID
- 2-s2.0-85139343747
- Other Identifier
- 991019173713704721
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- Collaboration types
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal