2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Sep 8;65(17):11703-11725. doi: 10.1021/acs.jmedchem.2c00534.
Michał Abram 1,  Marcin Jakubiec 1,  Katelyn Reeb 2,  Mary Hongying Cheng 3,  Robin Gedschold 4,  Anna Rapacz 5,  Szczepan Mogilski 5,  Katarzyna Socała 6,  Dorota Nieoczym 6,  Małgorzata Szafarz 7,  Gniewomir Latacz 8,  Bartłomiej Szulczyk 9,  Justyna Kalinowska-Tłuścik 10,  Kinga Gawel 11,  Camila V Esguerra 12,  Elżbieta Wyska 7,  Christa E Müller 4,  Ivet Bahar 3,  Andréia C K Fontana 2,  Piotr Wlaź 6,  Rafał M Kamiński 1,  Krzysztof Kamiński 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688Krakow, Poland.
  • 2 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania19102, United States.
  • 3 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania15213, United States.
  • 4 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, D-53121Bonn, Germany.
  • 5 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688Krakow, Poland.
  • 6 Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, 20-033Lublin, Poland.
  • 7 Department of Pharmacokinetics and Physical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688Krakow, Poland.
  • 8 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688Krakow, Poland.
  • 9 Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Banacha 1B, 02-097Warsaw, Poland.
  • 10 Department of Crystal Chemistry and Crystal Physics, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387Krakow, Poland.
  • 11 Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8B, 20-090Lublin, Poland.
  • 12 Chemical Neuroscience Group, Centre for Molecular Medicine Norway, University of Oslo, Gaustadalléen 21, Forskningsparken, 0349Oslo, Norway.
PMID: 35984707 DOI: 10.1021/acs.jmedchem.2c00534
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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