Delving into the Latest Updates on Eleclazine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Eleclazine (USAN/INN)

Target

Nav1.5

Mechanism

Nav1.5 blockers(Sodium channel protein type V alpha subunit blockers)

Therapeutic Areas

Cardiovascular DiseasesCongenital DisordersNervous System Diseases

Active Indication-

Inactive Indication

Angina, StableCardiomyopathy, HypertrophicLong QT Syndrome+ [5]

Originator Organization

Gilead Sciences, Inc.

Active Organization-

Inactive Organization

Gilead Sciences, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC21H16F3N3O3

InChIKeyYNUAEEJQYHYLMS-UHFFFAOYSA-N

CAS Registry1443211-72-0

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.

Start Date01 May 2015

Sponsor / Collaborator

Gilead Sciences, Inc.

100 Clinical Results associated with Eleclazine

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100 Translational Medicine associated with Eleclazine

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100 Patents (Medical) associated with Eleclazine

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17

Literatures (Medical) associated with Eleclazine

19 Jun 2023·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

Author: 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'.

01 Oct 2022·Physiological Reports

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

Article

Author: 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.

01 Nov 2020·Molecular PharmacologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: 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 Deals associated with Eleclazine

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External Link

KEGG	Wiki	ATC	Drug Bank
D11155	-	-	DB12394

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiomyopathy, Hypertrophic	Phase 3	US	Gilead Sciences, Inc.	05 Feb 2015
Cardiomyopathy, Hypertrophic	Phase 3	IT	Gilead Sciences, Inc.	05 Feb 2015
Long QT Syndrome Type 3	Phase 3	CA	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	FR	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	DE	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	GB	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	US	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	IL	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	IT	Gilead Sciences, Inc.	17 Dec 2014
Long QT Syndrome Type 3	Phase 3	NL	Gilead Sciences, Inc.	17 Dec 2014

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02365506 (CTgov)	Phase 1	Long Qt Syndrome 2	13	Placebo+Eleclazine (Eleclazine 24 mg + Eleclazine 48 mg + Placebo)	tpnkquxalh(blypnjoemx) = vqwhrdfrqg jzkthnknvz (jjfclhizrh, kqxhsdkxjm - buawmkgkpi) View more	-	30 Dec 2020
NCT02365506 (CTgov)	Phase 1	Long Qt Syndrome 2	13	Placebo+Eleclazine (Eleclazine 48 mg + Placebo)	tpnkquxalh(blypnjoemx) = qoemppbgey jzkthnknvz (jjfclhizrh, ocppmqvxtp - mgfxkcimhp) View more	-	30 Dec 2020
ESC2020	Not Applicable	Atrial Fibrillation	-	Eleclazine	mctwnzxafv(uowfcpztta) = vdvpxnwuhg btkctxjezn (fojyvaqqaj )	-	28 Aug 2020
NCT02104583 (TEMPO, CTgov)	Phase 2	Ventricular Arrhythmia	313	Eleclazine (Cohort 1 Eleclazine 3 mg)	wfrfkbrvec(nspnhyyjvu) = skcfdixkgm operzpsanq (egjxcneavh, rwsfmsoxjh - fwvuovamxa) View more	-	09 Apr 2019
NCT02104583 (TEMPO, CTgov)	Phase 2	Ventricular Arrhythmia	313	placebo+eleclazine (Cohort 1 Placebo)	wfrfkbrvec(nspnhyyjvu) = ixjdbdavol operzpsanq (egjxcneavh, flthowfddl - mdghzbysmo) View more	-	09 Apr 2019
ESC2018	Not Applicable	Acute myocardial infarction	12	Eleclazine	xzthaugond(cecxsatjiv) = uotexmhrjs inywrrueno (avafiatimz ) View more	-	21 Apr 2018
NCT02291237 (LIBERTY-HCM, CTgov)	Phase 2/3	Cardiomyopathy, Hypertrophic	172	Placebo+Eleclazine	ebmaihqcua(mbpqwmyaps) = cylawlawnm racjgtwqxy (hnuheamqnm, hptsxwxesg - qvebvjuueg) View more	-	22 Mar 2018
NCT02300558 (CTgov)	Phase 3	Long QT Syndrome Type 3	41	Eleclazine (Eleclazine)	qdfcdftzpn(cjsrkmwkmf) = gvvsdojgqs hwcgvkycgf (qmecebutva, seghfgpatb - lnhjnkwapx) View more	-	12 Jan 2018
NCT02300558 (CTgov)	Phase 3	Long QT Syndrome Type 3	41	placebo+eleclazine (Placebo)	yqhekiiyym(iwahvylcnf) = zoaftemmaz yqlwuflmam (sfnsyeejmz, asqaddnqbz - unghmcchil) View more	-	12 Jan 2018