Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late I Na i) of the cardiac Na V 1.5 channel with improved efficacy and potency relative to ranolazine

Koltun, Dmitry O.; Parkhill, Eric Q.; Elzein, Elfatih; Kobayashi, Tetsuya; Notte, Gregory T.; Kalla, Rao; Jiang, Robert H.; Li, Xiaofen; Perry, Thao; Avila, Belem; Wang, Weiqun; Smith-Maxwell, Catherine; Dhalla, Arvinder K.; Rajamani, Sridharan; Stafford, Brian; Tang, Jennifer; Mollova, Nevena; Belardinelli, Luiz; Zablocki, Jeff

doi:10.1016/j.bmcl.2016.03.101

Cited by 31 publications

(30 citation statements)

References 6 publications

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“…GS967 has been shown to preferentially inhibit persistent sodium current mediated by the cardiac voltage-gated sodium channel 17, 18 . GS967 has a long plasma half-life, excellent bioavailability, excellent brain penetration and is not metabolized 17, 19 . Recently, we have shown that GS967 exhibits antiepileptic activity in transgenic mice expressing a gain-of-function Scn2a mutation 20 .…”

Section: Introductionmentioning

confidence: 99%

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Anderson

Hawkins

Thompson

et al. 2017

Sci Rep

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Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a +/−) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a +/− mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker. Unexpectedly, GS967 significantly improved survival of Scn1a +/− mice and suppressed spontaneous seizures. By contrast, lamotrigine exacerbated the seizure phenotype. Electrophysiological recordings of acutely dissociated neurons revealed that chronic GS967-treatment had no impact on evoked action potential firing frequency of interneurons, but did suppress aberrant spontaneous firing of pyramidal neurons and was associated with significantly lower sodium current density. Lamotrigine had no effects on neuronal excitability of either neuron subtype. Additionally, chronically GS967-treated Scn1a +/− mice exhibited normalized pyramidal neuron sodium current density and reduced hippocampal NaV1.6 protein levels, whereas lamotrigine treatment had no effect on either pyramidal neuron sodium current or hippocampal NaV1.6 levels. Our findings demonstrate unexpected efficacy of a novel sodium channel blocker in Dravet syndrome and suggest a potential mechanism involving a secondary change in NaV1.6.

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Section: Introductionmentioning

confidence: 99%

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Anderson

Hawkins

Thompson

et al. 2017

Sci Rep

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“…GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)- [1,2,4]triazolo [4,3-a]pyridine (GS967; a triazolopyridine derivative) (Koltun et al, 2016) is a recently described sodium channel blocker that was originally demonstrated to exert potent antiarrhythmic effects in rabbit ventricular and canine atrial myocytes by a proposed mechanism of action involving preferential I NaL block Sicouri et al, 2013). More recently, GS967 was shown to suppress arrhythmogenicity evoked by ischemia (Bonatti et al, 2014), hypokalemia (Pezhouman et al, This work was supported by a Scientist Development Grant [11SDG5330006] from the American Heart Association (F.P.)…”

Section: Introductionmentioning

confidence: 99%

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

2016

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GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)- [1,2,4]triazolo [4,3-a]pyridine (GS967) is a recently described, novel, sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current. However, there has been no reported systematic investigation of the effects of this compound on isolated sodium channels. Here, we examined the effects of GS967 on peak (I NaP ) and late (I NaL ) sodium current recorded from cells that heterologously expressed human cardiac voltage-gated sodium channel, the principle cardiac sodium channel. As previously described, we observed that GS967 exerted tonic block of I NaL (63%) to a significantly greater extent than I NaP (19%). However, GS967 also caused a reduction of I NaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evoked more potent UDB of I NaP (IC 50 5 0.07 mM) than ranolazine (16 mM) and lidocaine (17 mM). Use-dependent block was best explained by a significant slowing of recovery from fast and slow inactivation with a significant enhancement of slow inactivation in the presence of GS967. Furthermore, GS967 was found to exert these same effects on a prototypical long QT syndrome mutation (delKPQ). An engineered mutation at an interaction site for local anesthetic agents (F1760A) partially attenuated the effect of GS967 on UDB, but had no effect on tonic I NaL block. We conclude that GS967 is a preferential inhibitor of I NaL , but it also exerts previously unreported strong effects on slow inactivation and recovery from inactivation, resulting in substantial UDB that is not entirely dependent on a known interaction site for local anesthetic agents.

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“…The discovered ease of rearrangement of dinitrotriazolo[4,3‐a]pyridines to corresponding triazolo[1,5‐a]pyridines should be stressed. It is well‐known that such Dimroth‐type process can be accomplished by heating with acid or base and is facilitated in case of electron‐withdrawing groups introduced into pyridine ring ,. In some cases the rearrangement of pyridine or pyrimidine derivatives occurs under relatively mild conditions, however, in the presence of nucleophiles, such as H 2 O or NH 3 .…”

Section: Resultsmentioning

confidence: 99%

“…Another important approach to [1,2,4]triazolo[1,5‐a]pyridine derivatives is recyclization of isomeric [1,2,4]triazolo[4,3‐a]pyridines via Dimroth rearrangement under acidic or basic conditions,, Scheme . These reactions are greatly facilitated by electron withdrawing groups (NO 2 , CF 3 , CHO, etc.)…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N‐Bridged 6,8‐Dinitrotriazolo[1,5‐a]pyridines

et al. 2019

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Facile and efficient protocols for the synthesis of 2- R-6,8-dinitro [1,2,4]triazolo[1,5-a]pyridines from commercially available starting materials have been developed. The reactions proceed via cyclization of corresponding 3,5-dinitropyridine-2-yl hydrazides or aldehyde 3,5-dinitropyridine-2-yl hydrazones followed by in situ Dimroth rearrangement to provide these triazole fused bicyclic heterocycles in good yields under mild conditions. Another synthetic route to target N-bridged dinitro [1,2,4] triazolo [1,5-a]pyridines includes arylation of 5-aryltetrazoles with 2-chloro-3,5-dinitropyridine and subsequent thermal decomposition/cyclization.

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Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late I Na i) of the cardiac Na V 1.5 channel with improved efficacy and potency relative to ranolazine

Cited by 31 publications

References 6 publications

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

Synthesis of N‐Bridged 6,8‐Dinitrotriazolo[1,5‐a]pyridines

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