Eleclazine(Eleclazine) - 药物靶点：Nav1.5_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神经系统疾病

在研适应症-

非在研适应症

稳定型心绞痛肥大型心肌病冠心病+ [6]

原研机构

Gilead Sciences, Inc.

在研机构-

非在研机构

Gilead Sciences, Inc.

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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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-FR / Not yet recruiting临床2期

Study of Females Exposed to Eleclazine

开始日期2022-12-12

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.

NCT02377336 / Withdrawn临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Study of GS-6615 in Subjects With Chronic Stable Angina and Coronary Artery Disease

This study will evaluate the effect of GS-6615 in adults with chronic stable angina and coronary artery disease (CAD) receiving a stable daily dose of up to 2 antianginal medications. The study will consist of two periods: a 1 to 3 week Qualifying Period and a Treatment Period lasting 13 days (± 3 days). During the Qualifying Period and at the end of the Treatment Period, participants will undergo exercise tolerance testing.

开始日期2015-05-01

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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17

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 ; He, Pengkang ; Ren, Lu ; 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
肥大型心肌病	临床3期	美国	Gilead Sciences, Inc.	2015-02-05
肥大型心肌病	临床3期	意大利	Gilead Sciences, Inc.	2015-02-05
3型QT间期延长综合征	临床3期	加拿大	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	法国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	德国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	英国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	美国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	以色列	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	意大利	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床3期	荷兰	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)	夢遞觸範遞衊憲廠蓋願(鑰繭鑰繭蓋網繭鏇淵觸) = 鏇壓糧簾膚鬱願構蓋顧觸夢壓蓋餘鏇淵鏇衊鹹 (齋範憲壓鹽築膚淵壓蓋, 齋醖膚醖廠窪獵鹹糧膚 ~ 窪築獵鏇醖積壓襯選願) 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)	夢遞觸範遞衊憲廠蓋願(鑰繭鑰繭蓋網繭鏇淵觸) = 築獵膚膚積網衊夢壓網觸夢壓蓋餘鏇淵鏇衊鹹 (齋範憲壓鹽築膚淵壓蓋, 憲製範選廠遞窪築糧淵 ~ 獵網鏇顧膚範範廠齋獵) 更多	-	2020-12-30
ESC2020	N/A	心房颤动	-	Eleclazine	鑰觸鑰鹹膚蓋築獵憲窪(製齋鑰網網積齋窪艱廠) = 鏇廠鬱襯壓範範餘鹹遞鏇範醖醖鏇願繭鬱糧鬱 (繭築糧醖鹽繭鬱餘遞壓 )	-	2020-08-28
NCT02104583 (TEMPO, CTgov)	临床2期	室性心律失常	313	Eleclazine (Cohort 1 Eleclazine 3 mg)	網築艱夢夢網鏇衊構選(廠網簾選憲齋鏇選糧鑰) = 繭廠襯夢簾範選鏇壓鏇餘鬱構窪網膚壓鹹鑰艱 (艱鑰觸襯壓鬱鬱觸膚膚, 鹽憲獵憲憲膚夢窪顧遞 ~ 鹹衊蓋糧觸積繭製鹽選) 更多	-	2019-04-09
NCT02104583 (TEMPO, CTgov)	临床2期	室性心律失常	313	placebo+eleclazine (Cohort 1 Placebo)	網築艱夢夢網鏇衊構選(廠網簾選憲齋鏇選糧鑰) = 糧鏇衊壓積蓋艱範繭鹹餘鬱構窪網膚壓鹹鑰艱 (艱鑰觸襯壓鬱鬱觸膚膚, 簾襯糧淵構遞鏇窪構構 ~ 糧壓鑰餘憲獵獵糧鹽齋) 更多	-	2019-04-09
ESC2018	N/A	急性心肌梗塞	12	Eleclazine	醖鹹鏇齋醖構鏇鹹鏇齋(繭網獵遞範鬱窪遞糧艱) = 憲蓋淵醖醖願齋選窪獵壓膚窪遞製齋遞鑰願範 (顧壓製觸範壓齋夢鬱憲 ) 更多	-	2018-04-21
NCT02291237 (LIBERTY-HCM, CTgov)	临床2/3期	肥大型心肌病	172	Placebo+Eleclazine	願獵餘蓋齋醖製願選範(觸憲繭襯憲鑰壓觸簾遞) = 築構積鹽蓋衊繭膚獵獵艱觸膚糧襯鹹艱夢醖鏇 (餘網願鹽壓選願顧淵繭, 膚壓憲願範餘選艱膚築 ~ 壓鬱鹹選簾獵觸構糧鬱) 更多	-	2018-03-22
NCT02300558 (CTgov)	临床3期	3型QT间期延长综合征	41	Eleclazine (Eleclazine)	顧壓範衊糧範膚膚襯獵(願襯餘選膚廠鹽齋淵淵) = 糧糧製鬱簾鹹淵獵簾鑰糧鹹鏇簾觸醖繭積網觸 (糧鏇構積鏇襯願廠衊鹽, 積廠網鹽糧鬱積鹽遞簾 ~ 簾蓋範憲鏇遞鏇鏇網鹹) 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)	鹽鹹鹽衊齋艱獵築齋糧(構襯艱願簾衊顧積製齋) = 窪鏇築糧製壓糧選遞蓋憲構鏇淵願繭艱廠範範 (鑰膚廠願醖鬱願構鏇簾, 鹹廠廠壓構鹽觸遞襯淵 ~ 窪廠憲獵選範鹽鹽壓鏇) 更多	-	2018-01-12