dc.date.accessioned |
2023-03-02T18:07:08Z |
|
dc.date.available |
2023-03-02T18:07:08Z |
|
dc.date.created |
2022-11-10T14:57:12Z |
|
dc.date.issued |
2022 |
|
dc.identifier.citation |
Abram, Michał Jakubiec, Marcin Reeb, Katelyn Cheng, Mary Hongying Gedschold, Robin Rapacz, Anna Mogilski, Szczepan Socała, Katarzyna Nieoczym, Dorota Szafarz, Małgorzata Latacz, Gniewomir Szulczyk, Bartłomiej Kalinowska-Tłuścik, Justyna Gawel, Kinga Aurelia Esguerra, Camila Wyska, Elżbieta Müller, Christa E. Bahar, Ivet Fontana, Andréia C. K. Wlaź, Piotr Kamiński, Rafał M. Kamiński, Krzysztof . 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. 2022, 65(17), 11703-11725 |
|
dc.identifier.uri |
http://hdl.handle.net/10852/100597 |
|
dc.description.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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dc.language |
EN |
|
dc.rights |
Attribution 4.0 International |
|
dc.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
|
dc.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 |
|
dc.title.alternative |
ENEngelskEnglishDiscovery 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 |
|
dc.type |
Journal article |
|
dc.creator.author |
Abram, Michał |
|
dc.creator.author |
Jakubiec, Marcin |
|
dc.creator.author |
Reeb, Katelyn |
|
dc.creator.author |
Cheng, Mary Hongying |
|
dc.creator.author |
Gedschold, Robin |
|
dc.creator.author |
Rapacz, Anna |
|
dc.creator.author |
Mogilski, Szczepan |
|
dc.creator.author |
Socała, Katarzyna |
|
dc.creator.author |
Nieoczym, Dorota |
|
dc.creator.author |
Szafarz, Małgorzata |
|
dc.creator.author |
Latacz, Gniewomir |
|
dc.creator.author |
Szulczyk, Bartłomiej |
|
dc.creator.author |
Kalinowska-Tłuścik, Justyna |
|
dc.creator.author |
Gawel, Kinga Aurelia |
|
dc.creator.author |
Esguerra, Camila |
|
dc.creator.author |
Wyska, Elżbieta |
|
dc.creator.author |
Müller, Christa E. |
|
dc.creator.author |
Bahar, Ivet |
|
dc.creator.author |
Fontana, Andréia C. K. |
|
dc.creator.author |
Wlaź, Piotr |
|
dc.creator.author |
Kamiński, Rafał M. |
|
dc.creator.author |
Kamiński, Krzysztof |
|
cristin.unitcode |
185,57,0,0 |
|
cristin.unitname |
Norsk Senter for Molekylærmedisin |
|
cristin.ispublished |
true |
|
cristin.fulltext |
original |
|
cristin.qualitycode |
2 |
|
dc.identifier.cristin |
2071997 |
|
dc.identifier.bibliographiccitation |
info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal of Medicinal Chemistry&rft.volume=65&rft.spage=11703&rft.date=2022 |
|
dc.identifier.jtitle |
Journal of Medicinal Chemistry |
|
dc.identifier.volume |
65 |
|
dc.identifier.issue |
17 |
|
dc.identifier.startpage |
11703 |
|
dc.identifier.endpage |
11725 |
|
dc.identifier.doi |
https://doi.org/10.1021/acs.jmedchem.2c00534 |
|
dc.type.document |
Tidsskriftartikkel |
|
dc.type.peerreviewed |
Peer reviewed |
|
dc.source.issn |
0022-2623 |
|
dc.type.version |
PublishedVersion |
|
dc.relation.project |
NFR/187615 |
|