GS967
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MedKoo CAT#: 510345

CAS#: 1262618-39-2

Description: GS967, also known as GS-458967, is a highly selective late sodium channel current blocker. The selective inhibition of late INa with GS967 can exert antiarrhythmic effects by suppressing EAD- and DAD-mediated extrasystolic activity in PFs and PV and SVC sleeve preparations. Selective late INa inhibition with GS967 exerts potent protective effects against ischemia-induced depolarization and repolarization abnormalities in both atria and ventricles.


Chemical Structure

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GS967
CAS# 1262618-39-2

Theoretical Analysis

MedKoo Cat#: 510345
Name: GS967
CAS#: 1262618-39-2
Chemical Formula: C14H7F6N3O
Exact Mass: 347.04933
Molecular Weight: 347.22
Elemental Analysis: C, 48.43; H, 2.03; F, 32.83; N, 12.10; O, 4.61

Price and Availability

Size Price Availability Quantity
5.0mg USD 85.0 Ready to ship
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 650.0 Ready to ship
200.0mg USD 1050.0 Ready to ship
500.0mg USD 1950.0 2 weeks
1.0g USD 2950.0 2 weeks
2.0g USD 5250.0 2 weeks
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Synonym: GS967; GS-967; GS 967; GS458967; GS 458967; GS-458967

IUPAC/Chemical Name: 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine

InChi Key: FEVBKJITJDHASC-UHFFFAOYSA-N

InChi Code: InChI=1S/C14H7F6N3O/c15-13(16,17)12-22-21-11-6-3-9(7-23(11)12)8-1-4-10(5-2-8)24-14(18,19)20/h1-7H

SMILES Code: FC(C1=NN=C2C=CC(C3=CC=C(OC(F)(F)F)C=C3)=CN21)(F)F

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: GS967 (GS458967) is an inhibitor of late INa with anti-arrhythmic actions.
In vitro activity: The application of 5 μM GS967 slightly reduced peak currents but strongly decreased persistent currents in all mutants tested (Fig. 3 b-h, i-k), while showed only a small effect on WT (Fig. 3a) overall confirming that GS967 binds directly to and interacts with the Nav1.1 protein. Scrutinizing activation and inactivation properties revealed that GS967 had no effect on activation parameters and slightly shifted the voltage of half-maximal inactivation 2–5 mV to more negative values for all mutants, except for F1774S for which GS967 shifted the half maximal inactivation voltage by about -16 mV (Additional file 1: Table S3). The most dramatic effect was seen for the process of recovery from inactivation, measured at  -90 mV. While WT and all mutants fully recovered within a few ms in the absence of GS967, the drug introduced an additional, and predominant, slow component with a time constant of 400–700 ms (Fig. 4). Reference: J Headache Pain. 2019; 20(1): 107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858687/
In vivo activity: In contrast, seizures in the GS967-treated Scn8aD/+ mice had a single tonic phase that terminated with post-ictal suppression. Combined analysis of video-EEG and video monitoring showed that Scn8aD/+ mice treated with GS967 had significantly lower seizure frequency, with 0.3 ± 0.2 seizures/24-hours in GS967-treated compared with 1.6 ± 0.4 seizures/24-hours in untreated mice (p < 0.004, Fig. 5C, Table 1). No seizures were observed in WT littermate mice (Table 1). These data demonstrate that GS967 has a potent anti-seizure effect in a mouse model of SCN8A encephalopathy. Reference: Epilepsia. 2018 Jun; 59(6): 1166–1176. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142814/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 32.5 93.6
DMF 25.0 72.0
DMF:PBS (pH 7.2) (1:2) 0.3 0.86
Ethanol 29.0 83.52

Preparing Stock Solutions

The following data is based on the product molecular weight 347.22 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Barbieri R, Bertelli S, Pusch M, Gavazzo P. Late sodium current blocker GS967 inhibits persistent currents induced by familial hemiplegic migraine type 3 mutations of the SCN1A gene. J Headache Pain. 2019 Nov 15;20(1):107. doi: 10.1186/s10194-019-1056-2. PMID: 31730442; PMCID: PMC6858687. 2. Ferrantini C, Pioner JM, Mazzoni L, Gentile F, Tosi B, Rossi A, Belardinelli L, Tesi C, Palandri C, Matucci R, Cerbai E, Olivotto I, Poggesi C, Mugelli A, Coppini R. Late sodium current inhibitors to treat exercise-induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium. Br J Pharmacol. 2018 Jul;175(13):2635-2652. doi: 10.1111/bph.14223. Epub 2018 May 3. PMID: 29579779; PMCID: PMC6003658. 3. Hézső T, Naveed M, Dienes C, Kiss D, Prorok J, Árpádffy-Lovas T, Varga R, Fujii E, Mercan T, Topal L, Kistamás K, Szentandrássy N, Almássy J, Jost N, Magyar J, Bányász T, Baczkó I, Varró A, Nánási PP, Virág L, Horváth B. Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium. Sci Rep. 2021 May 5;11(1):9565. doi: 10.1038/s41598-021-88903-3. PMID: 33953276; PMCID: PMC8100105. 4. Baker EM, Thompson CH, Hawkins NA, Wagnon JL, Wengert ER, Patel MK, George AL Jr, Meisler MH, Kearney JA. The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy. Epilepsia. 2018 Jun;59(6):1166-1176. doi: 10.1111/epi.14196. Epub 2018 May 21. PMID: 29782051; PMCID: PMC6142814.
In vitro protocol: 1. Barbieri R, Bertelli S, Pusch M, Gavazzo P. Late sodium current blocker GS967 inhibits persistent currents induced by familial hemiplegic migraine type 3 mutations of the SCN1A gene. J Headache Pain. 2019 Nov 15;20(1):107. doi: 10.1186/s10194-019-1056-2. PMID: 31730442; PMCID: PMC6858687. 2. Ferrantini C, Pioner JM, Mazzoni L, Gentile F, Tosi B, Rossi A, Belardinelli L, Tesi C, Palandri C, Matucci R, Cerbai E, Olivotto I, Poggesi C, Mugelli A, Coppini R. Late sodium current inhibitors to treat exercise-induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium. Br J Pharmacol. 2018 Jul;175(13):2635-2652. doi: 10.1111/bph.14223. Epub 2018 May 3. PMID: 29579779; PMCID: PMC6003658.
In vivo protocol: 1. Hézső T, Naveed M, Dienes C, Kiss D, Prorok J, Árpádffy-Lovas T, Varga R, Fujii E, Mercan T, Topal L, Kistamás K, Szentandrássy N, Almássy J, Jost N, Magyar J, Bányász T, Baczkó I, Varró A, Nánási PP, Virág L, Horváth B. Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium. Sci Rep. 2021 May 5;11(1):9565. doi: 10.1038/s41598-021-88903-3. PMID: 33953276; PMCID: PMC8100105. 2. Baker EM, Thompson CH, Hawkins NA, Wagnon JL, Wengert ER, Patel MK, George AL Jr, Meisler MH, Kearney JA. The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy. Epilepsia. 2018 Jun;59(6):1166-1176. doi: 10.1111/epi.14196. Epub 2018 May 21. PMID: 29782051; PMCID: PMC6142814.

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Hézső, T., Naveed, M., Dienes, C. et al. Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium. Sci Rep 11, 9565 (2021). https://doi.org/10.1038/s41598-021-88903-3

1: Bonatti R, Silva AF, Batatinha JA, Sobrado LF, Machado AD, Varone BB, Nearing BD, Belardinelli L, Verrier RL. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm. 2014 Oct;11(10):1827-35. doi: 10.1016/j.hrthm.2014.06.017. Epub 2014 Jun 17. PubMed PMID: 24953379.

2: Anderson LL, Thompson CH, Hawkins NA, Nath RD, Petersohn AA, Rajamani S, Bush WS, Frankel WN, Vanoye CG, Kearney JA, George AL Jr. Antiepileptic activity of preferential inhibitors of persistent sodium current. Epilepsia. 2014 Aug;55(8):1274-83. doi: 10.1111/epi.12657. Epub 2014 May 23. PubMed PMID: 24862204; PubMed Central PMCID: PMC4126848.

3: Fernandes S, Hoyer K, Liu G, Wang WQ, Dhalla AK, Belardinelli L, Rajamani S. Selective inhibition of the late sodium current has no adverse effect on electrophysiological or contractile function of the normal heart. J Cardiovasc Pharmacol. 2014 Jun;63(6):512-9. doi: 10.1097/FJC.0000000000000075. PubMed PMID: 24406487.

4: Pezhouman A, Madahian S, Stepanyan H, Ghukasyan H, Qu Z, Belardinelli L, Karagueuzian HS. Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts. Heart Rhythm. 2014 Mar;11(3):492-501. doi: 10.1016/j.hrthm.2013.11.026. Epub 2013 Nov 28. PubMed PMID: 24291413; PubMed Central PMCID: PMC3963462.

5: Trenor B, Gomis-Tena J, Cardona K, Romero L, Rajamani S, Belardinelli L, Giles WR, Saiz J. In silico assessment of drug safety in human heart applied to late sodium current blockers. Channels (Austin). 2013 Jul-Aug;7(4):249-62. PubMed PMID: 23696033; PubMed Central PMCID: PMC3989354.

6: Sicouri S, Belardinelli L, Antzelevitch C. Antiarrhythmic effects of the highly selective late sodium channel current blocker GS-458967. Heart Rhythm. 2013 Jul;10(7):1036-43. doi: 10.1016/j.hrthm.2013.03.023. Epub 2013 Mar 22. PubMed PMID: 23524321; PubMed Central PMCID: PMC3836836.

7: Belardinelli L, Liu G, Smith-Maxwell C, Wang WQ, El-Bizri N, Hirakawa R, Karpinski S, Li CH, Hu L, Li XJ, Crumb W, Wu L, Koltun D, Zablocki J, Yao L, Dhalla AK, Rajamani S, Shryock JC. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther. 2013 Jan;344(1):23-32. doi: 10.1124/jpet.112.198887. Epub 2012 Sep 25. PubMed PMID: 23010360.

 

GS967

5.0mg / USD 85.0


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