E-2730(E-2730) - 药物靶点：GAT1_在研适应症：癫痫发作_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

GAT1

作用机制

GAT1抑制剂(GABA转运蛋白1抑制剂)、突触传递调节器

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

4

项与 E-2730 相关的临床试验

NCT04676685 / Completed临床1期

A Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose and Single Dose Food Effect Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2730 in Healthy Subjects

The primary purpose of the study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of E2730 of multiple ascending oral doses in healthy adult participants and to assess the differences in PK, safety, and tolerability of E2730 between healthy Japanese and non-Japanese participants following multiple doses. This study will also determine the effect of food on PK of E2730.

开始日期2020-12-16

申办/合作机构

Eisai, Inc.

NCT03603639 / Terminated临床2期

A Multicenter, Double-Blind, Randomized, Cross-Over Study Evaluating Pharmacodynamic Activity of E2730 in Adult Subjects With Photosensitive Epilepsy

The primary purpose of the study is to assess the pharmacodynamic (PD) activity of E2730 as measured by suppression of epileptic photoparoxysmal response (PPR) in the participant's most sensitive eye condition in participants with photosensitive epilepsy.

开始日期2018-07-27

申办/合作机构

Eisai, Inc.

NCT03451890 / Completed临床1期

A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of E2730 in Healthy Subjects

This study will be conducted to evaluate the safety, tolerability, and pharmacokinetics of single ascending oral doses of E2730 in healthy adult participants.

开始日期2018-02-09

申办/合作机构

Eisai, Inc.

100 项与 E-2730 相关的临床结果

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100 项与 E-2730 相关的转化医学

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100 项与 E-2730 相关的专利（医药）

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4

项与 E-2730 相关的文献（医药）

2024-05-01·Epilepsy Research

Pharmacological evaluation of E2730, a novel selective uncompetitive GAT1 inhibitor, on epileptiform activities in resected brain tissues from human focal cortical dysplasia ex vivo

Article

作者: Kakita, Akiyoshi ; Kitaura, Hiroki ; Fukushima, Kazuyuki ; Ito, Yosuke ; Fukuda, Masafumi

Focal cortical dysplasia (FCD) is an important etiology of focal epilepsy in children and adults. However, only a few preclinical models sufficiently reproduce the characteristic histopathologic features of FCD. To improve the success rate of clinical trials for antiseizure medications (ASMs) in patients with FCD, more human-relevant preclinical models are needed, and epileptic foci resected from patients are a powerful tool for this purpose. Here, we conducted ex vivo studies using epileptic foci resected from patients with FCD type II to evaluate the pharmacologic effects of the ASM candidate E2730, a selective uncompetitive inhibitor of γ-aminobutyric acid transporter 1. We used the same ex vivo assay system to assess carbamazepine (CBZ), an ASM often prescribed for focal epilepsy, as a reference. At the higher dose tested (200 µM), both E2730 and CBZ suppressed spontaneous epileptiform activities almost completely. At the lower dose (100 µM), CBZ reduced the area of brain tissue showing epileptiform activity, whereas E2730 significantly decreased the number of epileptiforms. These findings suggest that E2730-both as a single agent and in combination with CBZ-merits evaluation in clinical trials involving patients with FCD.

2023-10-01·Epilepsia

E2730, an uncompetitive γ-aminobutyric acid transporter-1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy.

Article

作者: Haskali, Mohammad B ; Major, Brendan ; Vivash, Lucy ; Jones, Nigel C ; Casillas-Espinosa, Pablo M ; Fukushima, Kazuyuki ; Hudson, Matthew R ; Cheng, Jocelyn Y ; Shultz, Sandy R ; Silva, Juliana ; Jupp, Bianca ; Thergarajan, Peravina ; Wright, David K ; Kwan, Patrick ; O'Brien, Terence J ; Brady, Rhys D ; Yamakawa, Glenn R ; Ali, Idrish ; Braine, Emma ; Sachdev, Pallavi ; Mychasiuk, Richelle

OBJECTIVEMore than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild-to-moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ-aminobutyric acid transporter-1, and to test its seizure suppression effects in a rat model of chronic MTLE.METHODSWe first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid-induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video-electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures.RESULTSPlasma levels following continuous infusion of E2730 showed a clear dose-related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose-dependent manner, with 65% of rats becoming seizure-free at the highest dose tested. Mean seizure class did not differ between the treatment groups.SIGNIFICANCEThis study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose-dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.

2023-09-01·Epilepsia open

Discovery of E2730, a novel selective uncompetitive GAT1 inhibitor, as a candidate for anti-seizure medication.

Article

作者: Jensen, Frances E ; Song, Yeri ; Kosasa, Takashi ; Watanabe, Naoto ; Fukushima, Kazuyuki ; Higashiyama, Hiroyuki ; Roberts, Nicholas S ; Ito, Yoshimasa ; Hanada, Takahisa ; Hashimoto, Keisuke ; Talos, Delia M ; Furuya, Yoshiaki ; Ido, Katsutoshi ; Kazuta, Yuji ; Wu, Ting

OBJECTIVEAs of 2022, 36 anti-seizure medications (ASMs) have been licensed for the treatment of epilepsy, however, adverse effects (AEs) are commonly reported. Therefore, ASMs with a wide margin between therapeutic effects and AEs are preferred over ASMs that are associated with a narrow margin between efficacy and risk of AEs. E2730 was discovered using in vivo phenotypic screening and characterized as an uncompetitive, yet selective, inhibitor of γ-aminobutyric acid (GABA) transporter 1 (GAT1). Here, we describe the preclinical characteristics of E2730.METHODSAnti-seizure effects of E2730 were evaluated in several animal models of epilepsy: corneal kindling, 6 Hz-44 mA psychomotor seizure, amygdala kindling, Fragile X syndrome, and Dravet syndrome models. Effects of E2730 on motor coordination were assessed in accelerating rotarod tests. The mechanism of action of E2730 was explored by [³ H]E2730 binding assay. The GAT1-selectivity over other GABA transporters was examined by GABA uptake assay of GAT1, GAT2, GAT3, or betaine/GABA transporter 1 (BGT-1) stably expressing HEK293 cells. To further investigate the mechanism for E2730-mediated inhibition of GAT1, in vivo microdialysis and in vitro GABA uptake assays were conducted under conditions of different GABA concentrations.RESULTSE2730 showed anti-seizure effects in the assessed animal models with an approximately >20-‍fold margin between efficacy and motor incoordination. [³ H]E2730 binding on brain synaptosomal membrane was abolished in GAT1-deficient mice, and E2730 selectively inhibited GAT1-mediated GABA uptake over other GABA transporters. In addition, results of GABA uptake assays showed that E2730-mediated inhibition of GAT1 positively correlated to the level of ambient GABA in vitro. E2730 also increased extracellular GABA concentration in hyperactivated conditions but not under basal levels in vivo.SIGNIFICANCEE2730 is a novel, selective, uncompetitive GAT1 inhibitor, which acts selectively under the condition of increasing synaptic activity, contributing to a wide margin between therapeutic effect and motor incoordination.

100 项与 E-2730 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
癫痫发作	临床前	日本	Eisai Co., Ltd.	2023-05-18
反射性癫痫	临床前	美国	Eisai, Inc.	2018-07-27

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03603639 (CTgov)	临床2期	反射性癫痫	6	placebo+E2730 (Treatment A: Placebo)	鏇簾壓簾蓋鏇膚糧衊獵(構構窪鏇構製顧築簾繭) = 範廠觸鏇簾艱夢範齋廠齋構襯膚製顧齋鹽願壓 (網鏇構衊鑰顧窪鑰築餘, 願夢鑰願獵範鏇願築夢 ~ 鏇憲積願窪衊製鏇糧鹹) 更多	-	2022-05-04
				E2730 (Treatment B: E2730 40 mg)	鏇簾壓簾蓋鏇膚糧衊獵(構構窪鏇構製顧築簾繭) = 製顧獵淵鬱壓糧齋餘獵齋構襯膚製顧齋鹽願壓 (網鏇構衊鑰顧窪鑰築餘, 衊製襯鏇窪願鏇廠網餘 ~ 鏇衊衊廠憲壓範夢製繭) 更多