(Eleclazine) - 药物靶点：Nav1.5_在研适应症：长QT综合征3型_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Eleclazine (USAN/INN)

靶点

Nav1.5

作用机制

Nav1.5阻滞剂(V型钠通道蛋白α亚基阻滞剂)

治疗领域

心血管疾病遗传病与畸形

在研适应症

长QT综合征3型

非在研适应症

稳定型心绞痛肥大型心肌病冠心病+ [4]

原研机构

Gilead Sciences, Inc.

在研机构

Gilead Sciences, Inc.

非在研机构-

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C21H16F3N3O3

InChIKeyYNUAEEJQYHYLMS-UHFFFAOYSA-N

CAS号1443211-72-0

关联

11

项与 Eleclazine 相关的临床试验

EUCTR2019-003958-86-DK / Not yet recruiting临床2期

Study of Females Exposed to Eleclazine

开始日期2022-06-29

申办/合作机构

Gilead Sciences, Inc.

NCT02365506 / Completed临床1期

A Double-blind, Placebo-controlled Study to Evaluate the Effect of GS-6615 on QT, Safety and Tolerability in Subjects With Long QT2 Syndrome

The primary objective of the study is to evaluate the effect of oral eleclazine (formerly GS-6615) on corrected QT (QTc) interval in participants with long QT2 syndrome.

开始日期2015-07-20

申办/合作机构

Gilead Sciences, Inc.

NCT02441829 / Completed临床1期

A Phase 1 Open-Label, Parallel-Group, Adaptive, Single Dose Study to Evaluate the Pharmacokinetics of GS-6615 in Subjects With Normal and Impaired Renal Function

This study will evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of eleclazine and its metabolite, GS-623134, in participants with normal and impaired renal function. Participants in the healthy control group will be matched to participants with impaired renal function by age (± 5 years), gender, and body mass index (± 10%).

开始日期2015-05-31

申办/合作机构

Gilead Sciences, Inc.

100 项与 Eleclazine 相关的临床结果

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100 项与 Eleclazine 相关的转化医学

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100 项与 Eleclazine 相关的专利（医药）

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15

项与 Eleclazine 相关的文献（医药）

2023-06-19·Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Late sodium current in synergism with Ca²⁺/calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation.

Article

作者: Yang, Qiaomei ; Wei, Xiaohong ; Ren, Lu ; He, Pengkang ; Li, Gang ; Liu, Xiaoyan ; Yu, Shandong ; Huo, Yong ; Thai, Phung N ; Wu, Lin

Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late I_Na) and Ca²⁺/calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in β-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Na_v1.5 and phospho-CaMKII protein levels and late I_Na by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied (p < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Na_v1.5 and CaMKII, and reversed the increase of late I_Na (p < 0.05) in a synergistic mode. Overall, late I_Na in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late I_Na and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

2022-10-01·Physiological Reports

QT_c interval and ventricular action potential prolongation in the Mecp2^Null/+ murine model of Rett syndrome

Article

作者: James, Andrew F. ; Abdala, Ana P. ; Cheng, Hongwei ; Charles, Ian ; Hancox, Jules C.

AbstractRett Syndrome (RTT) is a congenital, X‐chromosome‐linked developmental disorder characterized by developmental delay, dysautonomia, and breathing irregularities. RTT is also associated with sudden death and QT intervals are prolonged in some RTT patients. Most individuals with RTT have mutations in the MECP2 gene. Whilst there is some evidence for QT prolongation in mouse models of RTT, there is comparatively little information on how loss of Mecp2 function affects ventricular action potentials (APs) and, to‐date, none on ventricular APs from female RTT mice. Accordingly, the present study was conducted to determine ECG and ventricular AP characteristics of Mecp2Null/+ female mice. ECG recordings from 12–13 month old female Mecp2Null/+ mice showed prolonged rate corrected QT (QTc) intervals compared to wild‐type (WT) controls. Although Mecp2Null/+ animals exhibited longer periods of apnoea than did controls, no correlation between apnoea length and QTc interval was observed. Action potentials (APs) from Mecp2Null/+ myocytes had longer APD90 values than those from WT myocytes and showed augmented triangulation. Application of the investigational INa,Late inhibitor GS‐6615 (eleclazine; 10 μM) reduced both APD90 and AP triangulation in Mecp2Null/+ and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2Null/+ myocytes and provide further evidence that GS‐6615 may have potential as an intervention against QT prolongation in RTT.

2020-11-01·Molecular Pharmacology3区 · 医学

GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

3区 · 医学

Article

作者: Burridge, Paul W ; Potet, Franck ; George, Alfred L ; Egecioglu, Defne E

GS-967 and eleclazine (GS-6615) are novel sodium channel inhibitors exhibiting antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current (I _NaL). Here, we took advantage of a high throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (I _NaP) recorded from human induced pluripotent stem cell-derived cardiomyocytes. We compared the effects of GS-967 and eleclazine with the antiarrhythmic drug lidocaine, the prototype I _NaL inhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. In human induced pluripotent stem cell-derived cardiomyocytes, GS-967 and eleclazine caused a reduction of I _NaP in a frequency-dependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB of I _NaP (IC₅₀ = 0.07 and 0.6 µM, respectively) than ranolazine (7.8 µM), lidocaine (133.5 µM), and lacosamide (158.5 µM). In addition, GS-967 and eleclazine exerted more potent effects on slow inactivation and recovery from inactivation compared with the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the higher association rates and moderate unbinding rate of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine. SIGNIFICANCE STATEMENT: We investigated the molecular pharmacology of GS-967 and eleclazine on sodium channels in human induced pluripotent stem cell-derived cardiomyocytes using a high throughput automated electrophysiology platform. Sodium channel inhibition by GS-967 and eleclazine has unique effects, including accelerating the onset of slow inactivation and impairing recovery from inactivation. These effects combined with rapid binding and moderate unbinding kinetics explain potent use-dependent block, which we propose contributes to their observed antiarrhythmic efficacy.

100 项与 Eleclazine 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11155	-	-	DB12394

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
长QT综合征3型	临床3期	-	Gilead Sciences, Inc.	-
3型QT间期延长综合征	临床2期	意大利	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床2期	美国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床2期	荷兰	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床1期	英国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床1期	西班牙	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床1期	以色列	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床1期	法国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床1期	芬兰	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床1期	德国	Gilead Sciences, Inc.	2014-12-17

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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


NCT02365506 (CTgov)	临床1期	QT间期延长综合征2	13	placebo+Eleclazine (Eleclazine 24 mg + Eleclazine 48 mg + Placebo)	鏇獵構範夢網夢窪鏇醖(積網願顧膚積鏇築膚製) = 構製襯膚蓋鹹廠壓顧襯選齋膚鏇糧糧淵顧壓襯 (鏇製構衊餘膚醖鬱膚獵, 網膚簾鏇壓淵網築鏇獵 ~ 衊鹽窪簾餘衊築膚淵構) 更多	-	2020-12-30
NCT02365506 (CTgov)	临床1期	QT间期延长综合征2	13	placebo+Eleclazine (Eleclazine 48 mg + Placebo)	鏇獵構範夢網夢窪鏇醖(積網願顧膚積鏇築膚製) = 鏇遞蓋襯窪夢鬱襯醖壓選齋膚鏇糧糧淵顧壓襯 (鏇製構衊餘膚醖鬱膚獵, 遞淵糧膚網顧醖範鹹選 ~ 遞鬱廠鹹膚範範糧憲積) 更多	-	2020-12-30
NCT02300558 (CTgov)	临床3期	3型QT间期延长综合征	41	Eleclazine (Eleclazine)	鏇膚選遞獵壓醖壓憲繭(網繭範衊鬱餘鏇鏇願簾) = 繭鹽積遞鏇壓範鑰遞範選醖憲衊築網選願鏇觸 (遞齋遞膚範觸鹽遞選夢, 獵襯遞壓齋鏇鬱齋膚範 ~ 網廠憲膚積淵艱襯淵夢) 更多	-	2018-01-12
NCT02300558 (CTgov)	临床3期	3型QT间期延长综合征	41	placebo+eleclazine (Placebo)	餘夢糧鏇繭糧繭蓋願餘(願壓淵憲艱醖鬱夢蓋積) = 獵淵襯襯選齋齋顧繭遞糧齋鹽築遞構齋獵顧鹽 (膚齋簾顧壓淵餘襯鹽鬱, 襯齋鏇範積鹽範糧艱鏇 ~ 糧窪觸鬱憲壓鬱願積遞) 更多	-	2018-01-12
NCT02291237 (CTgov)	临床2/3期	肥大型心肌病	172	placebo+Eleclazine	艱齋積壓夢願鹹網繭淵(廠糧糧齋淵淵餘網積築) = 餘觸衊遞鹽壓築蓋獵製遞鹽襯鑰構糧顧製簾願 (憲獵壓鹽窪蓋遞積範構, 鬱築獵鏇範繭醖淵獵構 ~ 願鏇範製範醖糧夢鏇積) 更多	-	2018-03-22
ESC2020	N/A	心房颤动	-	Eleclazine	範夢願衊簾夢築齋製艱(繭衊窪築築網廠鑰膚積) = 繭餘選糧網衊淵鏇蓋觸廠鹽淵範膚積鑰網衊鏇 (觸製鑰繭糧選壓鑰網繭 )	-	2020-08-28
NCT02104583 (CTgov)	临床2期	室性心律失常	313	Eleclazine (Cohort 1 Eleclazine 3 mg)	淵窪廠糧夢窪壓願衊鹽(齋蓋繭淵築憲鏇蓋鏇壓) = 膚糧淵鹹艱餘鹽夢範憲窪範網鑰繭蓋艱廠壓鹽 (繭鏇夢餘蓋壓壓積顧積, 齋壓膚鑰艱積鬱簾鬱鑰 ~ 襯網餘膚鹹遞簾網壓糧) 更多	-	2019-04-09
NCT02104583 (CTgov)	临床2期	室性心律失常	313	placebo+eleclazine (Cohort 1 Placebo)	淵窪廠糧夢窪壓願衊鹽(齋蓋繭淵築憲鏇蓋鏇壓) = 齋製艱膚繭構壓襯襯積窪範網鑰繭蓋艱廠壓鹽 (繭鏇夢餘蓋壓壓積顧積, 廠積觸觸範糧鹹遞夢齋 ~ 夢繭齋鬱憲蓋淵鑰餘選) 更多	-	2019-04-09
ESC2018	N/A	急性心肌梗塞	12	Eleclazine	鏇鹽築鑰襯構築鹹製願(壓積鏇築範膚膚廠遞醖) = 夢製淵憲願觸憲遞壓齋餘醖蓋襯網鏇範鏇糧膚 (鑰鏇獵觸淵齋鏇選壓鑰 ) 更多	-	2018-04-21