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Journal article
Discovery of (R)‑N‑Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS‑1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo
Journal of medicinal chemistry, v 65(17), pp 11703-11725
08 Sep 2022
PMID: 35984707
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
( R )-7 [( R )-AS-1] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. ( R )-7 [( R )-AS-1] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, ( R )-7 [( R )-AS-1] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.
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- Title
- Discovery of (R)‑N‑Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS‑1], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity In Vivo
- Creators
- Michał Abram - Faculty (United Kingdom)Marcin Jakubiec - Jagiellonian UniversityKatelyn Reeb - Drexel UniversityMary Hongying Cheng - University of PittsburghRobin Gedschold - University of BonnAnna Rapacz - Jagiellonian UniversitySzczepan Mogilski - Jagiellonian UniversityKatarzyna Socała - Maria Curie-Skłodowska UniversityDorota Nieoczym - Maria Curie-Skłodowska UniversityMałgorzata Szafarz - Jagiellonian UniversityGniewomir Latacz - Jagiellonian UniversityBartłomiej Szulczyk - Medical University of WarsawJustyna Kalinowska-Tłuścik - Jagiellonian UniversityKinga Gawel - Medical University of LublinCamila V. Esguerra - University of OsloElżbieta Wyska - Jagiellonian UniversityChrista E. Müller - University of BonnIvet Bahar - University of PittsburghAndréia C. K. Fontana - Drexel UniversityPiotr Wlaź - Maria Curie-Skłodowska UniversityRafał M. Kamiński - Faculty (United Kingdom)Krzysztof Kamiński - Faculty (United Kingdom)
- Publication Details
- Journal of medicinal chemistry, v 65(17), pp 11703-11725
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000854998300001
- Scopus ID
- 2-s2.0-85137399481
- Other Identifier
- 991020099916804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal