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发现（）--苄基-2-(2,5-二氧代吡咯烷-1-基)丙酰胺[]，一种具有口服生物利用度的新型 EAAT2 调节剂，具有类药性和强效抗癫痫活性。

Discovery of ()--Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity .

机构信息

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688Krakow, Poland.

Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania19102, United States.

出版信息

J Med Chem. 2022 Sep 8;65(17):11703-11725. doi: 10.1021/acs.jmedchem.2c00534. Epub 2022 Aug 19.

DOI:10.1021/acs.jmedchem.2c00534
PMID:35984707
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9469208/
Abstract

[] showed broad-spectrum antiseizure activity across 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. 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. [] 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 pharmacokinetic and absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, [] 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.

摘要

[] 在多种小鼠癫痫模型中表现出广谱抗癫痫活性：最大电休克（MES）、6 Hz（32/44 mA）、急性戊四氮（PTZ）和 PTZ 点燃。还观察到抗癫痫活性与中枢神经系统相关不良反应之间的显著分离。在原代神经胶质细胞培养物和表达谷氨酸转运体 EAAT2 的 COS-7 细胞中的研究表明，谷氨酸摄取增强，显示出立体选择性正变构调节剂（PAM）效应，分子对接模拟进一步支持了这一效应。[] 在 EAAT1 和 EAAT3 测定中不活跃，并且没有表现出明显的脱靶活性，包括与已上市抗癫痫药物报告的靶点的相互作用，表明其作用机制新颖且前所未有的。[] 的药代动力学和吸收、分布、代谢、排泄、毒性（ADME-Tox）特征均证实了该化合物具有良好的类药性潜力。因此，[] 可被视为 EAAT2 的首个小分子 PAM，有望在癫痫症和可能其他中枢神经系统疾病的进一步临床前和临床开发中得到应用。

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