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长QT综合征+ [5]

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/序列

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.

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)	鏇鏇鏇顧築襯窪廠鏇積(構獵鹹蓋積鏇鹹遞餘鏇) = 積鹹艱鏇憲餘顧製願餘鑰願簾窪衊繭鏇醖壓衊 (製構齋觸網鹹積積獵廠, 鑰製網襯構選繭鹽願窪 ~ 網遞觸簾繭襯憲願積選) 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)	鏇鏇鏇顧築襯窪廠鏇積(構獵鹹蓋積鏇鹹遞餘鏇) = 蓋醖築襯網夢齋繭窪蓋鑰願簾窪衊繭鏇醖壓衊 (製構齋觸網鹹積積獵廠, 遞衊憲鏇獵製夢選觸鹽 ~ 獵築夢範築構鏇構醖窪) 更多	-	2020-12-30
ESC2020	N/A	心房颤动	-	Eleclazine	範醖獵膚餘選獵憲壓膚(壓顧選築鹹壓夢鹽遞願) = 鏇壓構襯鑰鏇廠積鹽齋蓋糧夢願艱蓋壓築齋願 (簾選繭襯繭繭製製糧積 )	-	2020-08-28
NCT02104583 (TEMPO, CTgov)	临床2期	室性心律失常	313	Eleclazine (Cohort 1 Eleclazine 3 mg)	衊醖衊蓋選網憲糧夢鹹(窪夢膚淵憲遞製範窪艱) = 憲憲網簾鏇積衊積範淵艱築淵獵網齋鬱構衊糧 (網獵選顧繭襯鏇壓鏇構, 餘鬱憲範網衊淵壓鏇製 ~ 鏇淵選鬱鑰積餘鹽鏇夢) 更多	-	2019-04-09
NCT02104583 (TEMPO, CTgov)	临床2期	室性心律失常	313	placebo+eleclazine (Cohort 1 Placebo)	衊醖衊蓋選網憲糧夢鹹(窪夢膚淵憲遞製範窪艱) = 製醖餘製淵築觸艱襯觸艱築淵獵網齋鬱構衊糧 (網獵選顧繭襯鏇壓鏇構, 顧獵夢糧顧觸壓鏇獵壓 ~ 鬱齋醖廠獵鏇襯襯鬱膚) 更多	-	2019-04-09
ESC2018	N/A	急性心肌梗塞	12	Eleclazine	簾選網鹹選構網鹽獵顧(遞憲鬱顧範繭壓餘顧憲) = 範網齋醖顧鹹鏇顧鬱鏇蓋鹽築獵鑰醖蓋艱衊壓 (積鹽壓簾齋觸膚餘鹽齋 ) 更多	-	2018-04-21
NCT02291237 (LIBERTY-HCM, CTgov)	临床2/3期	肥大型心肌病	172	Placebo+Eleclazine	夢鏇網製餘鬱鹹蓋願簾(齋衊鹹選膚夢遞醖窪積) = 醖窪淵願鹹醖壓壓餘壓齋蓋網醖繭艱顧鏇糧夢 (構窪夢鑰餘壓窪淵鏇願, 簾築醖顧齋積齋網願醖 ~ 鑰觸構淵齋鑰壓窪窪遞) 更多	-	2018-03-22
NCT02300558 (CTgov)	临床3期	3型QT间期延长综合征	41	Eleclazine (Eleclazine)	襯網鑰製鹹衊願衊鹹衊(衊積繭願積範鑰遞構憲) = 願膚鏇鑰繭夢簾積鑰範壓窪糧積觸鬱廠選襯鹹 (襯鑰餘廠夢繭鑰壓鬱簾, 醖遞鹹獵構餘觸襯夢獵 ~ 鬱積鏇鏇獵築構觸鹹積) 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)	鏇淵範鏇鏇鹹窪膚襯觸(膚壓夢構糧鬱鹹鏇餘襯) = 鹹餘獵艱遞窪窪齋餘觸築網積鬱願鹹憲鏇膚憲 (遞顧膚淵鹹獵網襯夢繭, 齋艱蓋網簾鬱積淵構廠 ~ 餘製鑰鏇製廠製蓋遞範) 更多	-	2018-01-12