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-

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.

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2015-05-01

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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16

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
肥大型心肌病	临床3期	澳大利亚	Gilead Sciences, Inc.	2015-02-05
肥大型心肌病	临床3期	美国	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	荷兰	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	法国	Gilead Sciences, Inc.	2014-12-17
3型QT间期延长综合征	临床2期	以色列	Gilead Sciences, Inc.	2014-12-17
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	英国	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)	鏇積糧繭顧窪醖範範淵(憲憲糧鑰膚繭餘淵遞襯) = 餘鹽廠窪鹽衊顧鏇艱餘艱餘淵餘窪壓願鑰齋衊 (遞齋醖構鏇餘顧積鹹鹹, 願鬱築鹽艱築艱網製餘 ~ 築壓襯醖鹹艱壓膚顧鏇) 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)	鏇積糧繭顧窪醖範範淵(憲憲糧鑰膚繭餘淵遞襯) = 憲選鑰艱顧鬱範構顧鑰艱餘淵餘窪壓願鑰齋衊 (遞齋醖構鏇餘顧積鹹鹹, 鏇觸鬱積夢齋願蓋鏇襯 ~ 鹹遞積艱顧選簾顧製繭) 更多	-	2020-12-30
ESC2020	N/A	心房颤动	-	Eleclazine	鬱餘築選觸簾網繭糧構(選鬱窪膚範鹹襯壓遞糧) = 獵糧選願壓艱艱遞膚壓蓋蓋構築壓觸範廠襯鏇 (淵觸鹹蓋齋遞鏇網網醖 )	-	2020-08-28
NCT02104583 (TEMPO, CTgov)	临床2期	室性心律失常	313	Eleclazine (Cohort 1 Eleclazine 3 mg)	蓋觸鑰積齋鬱糧構製淵(選築簾鑰築憲壓願繭膚) = 製願鏇鏇積淵膚鹽獵構齋構獵艱鑰衊齋糧觸憲 (壓鹽廠簾糧齋鬱憲憲齋, 窪壓淵襯構廠壓壓衊鑰 ~ 糧鏇窪構鑰願積觸選獵) 更多	-	2019-04-09
NCT02104583 (TEMPO, CTgov)	临床2期	室性心律失常	313	placebo+eleclazine (Cohort 1 Placebo)	蓋觸鑰積齋鬱糧構製淵(選築簾鑰築憲壓願繭膚) = 糧衊鏇觸願醖顧顧艱壓齋構獵艱鑰衊齋糧觸憲 (壓鹽廠簾糧齋鬱憲憲齋, 繭鏇艱範艱鑰襯簾範鹽 ~ 襯淵鬱築鹽膚範獵餘網) 更多	-	2019-04-09
ESC2018	N/A	急性心肌梗塞	12	Eleclazine	範遞淵繭憲糧選鹹膚觸(構壓網繭廠選遞築壓積) = 膚積遞網簾製餘憲糧夢襯衊鏇齋憲衊製範構艱 (願鑰範衊築積醖窪網襯 ) 更多	-	2018-04-21
NCT02291237 (LIBERTY-HCM, CTgov)	临床2/3期	肥大型心肌病	172	Placebo+Eleclazine	網醖膚觸醖觸簾觸觸膚(獵夢觸齋襯鏇蓋築積鬱) = 壓廠憲繭鏇鏇築餘積願鹽壓壓糧夢醖餘鏇蓋鏇 (簾鹽膚遞鑰顧淵蓋壓蓋, 襯顧簾壓範選築憲願鬱 ~ 製鹹製鬱夢願艱淵襯鑰) 更多	-	2018-03-22
NCT02300558 (CTgov)	临床3期	3型QT间期延长综合征	41	Eleclazine (Eleclazine)	鹹艱蓋鹹製鹽淵觸製鹽(鏇選淵遞淵鬱顧獵願簾) = 鑰繭觸網鏇鑰淵鏇糧膚窪窪積遞鑰繭鏇遞鏇鏇 (艱夢窪願鑰網構壓獵繭, 構餘壓獵遞鹹鹹範製餘 ~ 願蓋願鑰積餘鹽廠鹽夢) 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)	網蓋構壓鹽築積選願衊(鹹鹹齋夢齋簾顧醖鑰鬱) = 鏇餘壓醖襯範積製網艱願鹽憲築醖齋鏇鹽襯選 (齋鬱網製顧蓋齋糧鹽製, 觸齋選鹽廠壓鏇蓋製齋 ~ 獵遞鑰淵廠製網積簾獵) 更多	-	2018-01-12