phkineticaФармакокинетика и ФармакодинамикаPharmacokinetics and Pharmacodynamics2587-78362686-8830ООО «Издательство ОКИ»10.37489/2587-7836-2022-3-3-9phkinetica-326Research ArticleАКТУАЛЬНЫЕ ОБЗОРЫCURRENT REVIEWSКардиопротекторные средства с биароматической структурой. Часть 3. Блокаторы натриевых каналовСardioprotective agents with biaromatic structure. Part 3. Sodium channel blockershttps://orcid.org/0000-0003-2617-0334МокровГ. В.MokrovG. V.

Мокров Григорий Владимирович к. х. н., в. н. с. лаборатории тонкого органического синтеза отдела химии лекарственных средств

SPIN-код: 8755-7666

Москва

Mokrov Grigory V. PhD, Cand. Sci. (Chemical), Leading researcher of the fine organic synthesis laboratory at the drug chemistry department 

SPIN code: 8755-7666

Moscow

g.mokrov@gmail.comФГБНУ «НИИ фармакологии имени В.В. Закусова»РоссияFSBI «Zakusov Institute of Pharmacology»Russian Federation2022201220220339Copyright © Мокров Г.В., 20222022Мокров Г.В.Mokrov G.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacokinetica.ru/jour/article/view/326

Настоящий обзор продолжает серию обзоров по анализу соединений с кардиопротекторными свойствами в ряду биароматических структур, к которым относится и ряд блокаторов натриевых каналов. Среди потенциал-зависимых натриевых каналов наиболее представленной в сердце является изоформа Nav1.5. Блокаторы натриевых каналов исторически получили название «антиаритмики I класса». Среди соединений этого типа биароматическое строение имеют преимущественно блокаторы позднего тока Nav1.5, относящиеся к подклассу Id антиаритмических средств. Лидерные молекулы из этой подгруппы, такие как ранолазин, GS-458967, и F15845 снижают время восстановления потенциала действия и подавляют триггерную активность, вызванную ранней постдеполяризацией. Они эффективны для лечения стабильной стенокардии и желудочковой тахикардии.

This review continues a series of reviews on the analysis of compounds with cardioprotective properties in a number of biaromatic structures, which include a range of sodium channel blockers. Among voltage-gated sodium channels, the Nav1.5 isoform is the most abundant in the heart. Sodium channel blockers have historically been called "class I antiarrhythmics". Among the compounds of this type, a biaromatic structure mainly have the Nav1.5 late current blockers belonging to the Id subclass of antiarrhythmic drugs. Leader molecules from this subgroup, such as ranolazine, GS-458967, and F15845, reduce action potential recovery time and suppress trigger activity induced by early post-depolarization. They are effective for the treatment of stable angina and ventricular tachycardia.

антиаритмикикардиопротекторыблокаторы Na-каналовбиароматические соединенияаntiarrhythmicscardioprotectorsNa-channels blockersbiaromatic compoundsReferencesМокров Г. В. Кардиопротекторные средства с биароматической структурой. Часть 1. Блокаторы кальциевых каналов. Фармакокинетика и фармакодинамика. 2021;(4):3–17. DOI: 10.37489/2587-7836-2021-4-3-17Mokrov GV. Сardioprotective agents with biaromatic structure. Part 1. Calcium channel blockers. Farmako-kinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2021;(4):3–17. (In Russ).. DOI: 10.37489/2587-7836-2021-4-3-17Мокров Г. В. Кардиопротекторные средства с биароматической структурой. Часть 2. Блокаторы HCN-каналов. Фармакокинетика и фармакодинамика. 2022;(2):03–10. DOI: 10.37489/2587-7836-2022-2-03-10Mokrov GV. Сardioprotective agents with biaromatic structure. Part 2. HCN channel blockers. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2022;(2):03–10. (In Russ). DOI: 10.37489/2587-7836-2022-2-03-10Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J Physiol. 2010;588(24):4969–4985. DOI: 10.1113/JPHYSIOL.2010.199034Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J Physiol. 2010;588(24):4969–4985. DOI: 10.1113/JPHYSIOL.2010.199034Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels. Pharmacol Rev. 2005;57(4):411–425. DOI: 10.1124/PR.57.4.5Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels. Pharmacol Rev. 2005;57(4):411–425. DOI: 10.1124/PR.57.4.5Hugues A. Roles and regulation of the cardiac sodium channel Nav1.5: Recent insights from experimental studies. Cardiovasc Res. 2007;76(3):381–389. DOI: 10.1016/J.CARDIORES.2007.07.019/2/76-3-381-FIG1.GIFHugues A. Roles and regulation of the cardiac sodium channel Nav1.5: Recent insights from experimental studies. Cardiovasc Res. 2007;76(3):381–389. DOI: 10.1016/J.CARDIORES.2007.07.019/2/76-3-381-FIG1.GIFRemme CA, Verkerk AO, Hoogaars WMH, et al. The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium. Basic Res Cardiol. 2009;104(5):511–522. DOI: 10.1007/S00395-009-0012-8/FIGURES/6Remme CA, Verkerk AO, Hoogaars WMH, et al. The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium. Basic Res Cardiol. 2009;104(5):511–522. DOI: 10.1007/S00395-009-0012-8/FIGURES/6Lei M, Wu L, Terrar DA, Huang CLH. Modernized classification of cardiac antiarrhythmic drugs. Circulation. 2018;138(17):1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455Lei M, Wu L, Terrar DA, Huang CLH. Modernized classification of cardiac antiarrhythmic drugs. Circulation. 2018;138(17):1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455Knollmann BC, Roden DM. Antiarrhythmic Drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw-Hill Education; 2017. http://accessmedicine.mhmedical.com/content.aspx?aid=1162538774Knollmann BC, Roden DM. Antiarrhythmic Drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw-Hill Education; 2017. http://accessmedicine.mhmedical.com/content.aspx?aid=1162538774Gillis A, Singh B, Smith T, et al. Cardiac Electrophysiology: From Cell to Bedside. (Zipes D JJ, ed.). Saunders; 4th edition; 2004.Gillis A, Singh B, Smith T, et al. Cardiac Electrophysiology: From Cell to Bedside. (Zipes D JJ, ed.). Saunders; 4th edition; 2004.Horváth B, Hézső T, Kiss D, et al. Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents. Front Pharmacol. 2020;11:413. DOI: 10.3389/FPHAR.2020.00413Horváth B, Hézső T, Kiss D, et al. Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents. Front Pharmacol. 2020;11:413. DOI: 10.3389/FPHAR.2020.00413Antzelevitch C, Nesterenko V, Shryock JC, Rajamani S, Song Y, Belardinelli L. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol. 2014;221:137–168. DOI: 10.1007/978-3-642-41588-3_7Antzelevitch C, Nesterenko V, Shryock JC, Rajamani S, Song Y, Belardinelli L. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol. 2014;221:137–168. DOI: 10.1007/978-3-642-41588-3_7Kluge AF, Clark RD, Strosberg AM, Pascal JCG, Whiting R. US Patent 4567264. Published online 1986.Kluge AF, Clark RD, Strosberg AM, Pascal JCG, Whiting R. US Patent 4567264. Published online 1986.Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol. 1992;20(1):131–138.Cocco G, Rousseau MF, Bouvy T, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol. 1992;20(1):131–138.Reed M, Kerndt CC, Gopal S, Nicolas D. Ranolazine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. StatPearls Publishing; 2021. Accessed October 12, 2021. https://www.ncbi.nlm.nih.gov/books/ NBK507828/Reed M, Kerndt CC, Gopal S, Nicolas D. Ranolazine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. StatPearls Publishing; 2021. Accessed October 12, 2021. https://www.ncbi.nlm.nih.gov/books/ NBK507828/Bazoukis G, Tse G, Letsas KP, et al. Impact of ranolazine on ventricular arrhythmias – A systematic review. J Arrhythmia. 2018;34(2):124–128. DOI: 10.1002/JOA3.12031Bazoukis G, Tse G, Letsas KP, et al. Impact of ranolazine on ventricular arrhythmias – A systematic review. J Arrhythmia. 2018;34(2):124–128. DOI: 10.1002/JOA3.12031López-Ortiz M, Monsalvo I, Demare P, et al. Synthesis of Ranolazine Derivatives Containing the (1S,4S)-2,5-Diazabicyclo[2.2.1]Heptane Moiety and Their Evaluation as Vasodilating Agents. Chem Biol Drug Des. 2014;83(6):710–720. DOI: 10.1111/CBDD.12285López-Ortiz M, Monsalvo I, Demare P, et al. Synthesis of Ranolazine Derivatives Containing the (1S,4S)-2,5-Diazabicyclo[2.2.1]Heptane Moiety and Their Evaluation as Vasodilating Agents. Chem Biol Drug Des. 2014;83(6):710–720. DOI: 10.1111/CBDD.12285Garner JA, Hearse DJ, Bernier M. R56865, a potent new antiarrhythmic agent, effective during ischemia and reperfusion in the rat heart. J Cardiovasc Pharmacol. 1990;16(3):468–479. DOI: 10.1097/00005344-199009000-00018Garner JA, Hearse DJ, Bernier M. R56865, a potent new antiarrhythmic agent, effective during ischemia and reperfusion in the rat heart. J Cardiovasc Pharmacol. 1990;16(3):468–479. DOI: 10.1097/00005344-199009000-00018Le Grand B, Coulombe A, John GW. Late sodium current inhibition in human isolated cardiomyocytes by R 56865. J Cardiovasc Pharmacol. 1998;31(5):800–804. DOI: 10.1097/00005344-199805000-00021Le Grand B, Coulombe A, John GW. Late sodium current inhibition in human isolated cardiomyocytes by R 56865. J Cardiovasc Pharmacol. 1998;31(5):800–804. DOI: 10.1097/00005344-199805000-00021Létienne R, Vié B, Le Grand B. Pharmacological characterisation of sodium channels in sinoatrial node pacemaking in the rat heart. Eur J Pharmacol. 2006;530(3):243–249. DOI: 10.1016/J.EJPHAR.2005.11.035Létienne R, Vié B, Le Grand B. Pharmacological characterisation of sodium channels in sinoatrial node pacemaking in the rat heart. Eur J Pharmacol. 2006;530(3):243–249. DOI: 10.1016/J.EJPHAR.2005.11.035Himmel HM, Wilhelm D, Ravens U. Effects of R56865 on membrane currents in isolated ventricular cardiomyocytes of the guinea-pig. Eur J Pharmacol. 1990;187(2):235–240. DOI: 10.1016/0014-2999(90)90010-4Himmel HM, Wilhelm D, Ravens U. Effects of R56865 on membrane currents in isolated ventricular cardiomyocytes of the guinea-pig. Eur J Pharmacol. 1990;187(2):235–240. DOI: 10.1016/0014-2999(90)90010-4Kehrbach W, Mlinaric M, Ziegler D, Brueckner R, Bielenberg W. US Patent 5547967. Published online 1996.Kehrbach W, Mlinaric M, Ziegler D, Brueckner R, Bielenberg W. US Patent 5547967. Published online 1996.John GW, Létienne R, Grand B Le, et al. KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic Properties. Cardiovasc Drug Rev. 2004;22(1):17–26. DOI: 10.1111/J.1527-3466.2004.TB00129.XJohn GW, Létienne R, Grand B Le, et al. KC 12291: An Atypical Sodium Channel Blocker with Myocardial Antiischemic Properties. Cardiovasc Drug Rev. 2004;22(1):17–26. DOI: 10.1111/J.1527-3466.2004.TB00129.XDecking UKM, Hartmann M, Rose H, Brückner R, Meil J, Schrader J. Cardioprotective actions of KC 12291 I. Inhibition of voltage-gated Na+ channels in ischemia delays myocardial Na+ overload. Naunyn Schmiedebergs Arch Pharmacol. 1998;358(5):547–553. DOI: 10.1007/PL00005291Decking UKM, Hartmann M, Rose H, Brückner R, Meil J, Schrader J. Cardioprotective actions of KC 12291 I. Inhibition of voltage-gated Na+ channels in ischemia delays myocardial Na+ overload. Naunyn Schmiedebergs Arch Pharmacol. 1998;358(5):547–553. DOI: 10.1007/PL00005291Le Grand B, Pignier C, Létienne R, et al. Sodium late current blockers in ischemia reperfusion: is the bullet magic? J Med Chem. 2008;51(13):3856–3866. DOI: 10.1021/JM800100ZLe Grand B, Pignier C, Létienne R, et al. Sodium late current blockers in ischemia reperfusion: is the bullet magic? J Med Chem. 2008;51(13):3856–3866. DOI: 10.1021/JM800100ZCatterall WA. From Ionic Currents to Molecular Mechanisms: The Structure and Function of Voltage-Gated Sodium Channels. Neuron. 2000;26(1):13–25. DOI: 10.1016/S0896-6273(00)81133-2Catterall WA. From Ionic Currents to Molecular Mechanisms: The Structure and Function of Voltage-Gated Sodium Channels. Neuron. 2000;26(1):13–25. DOI: 10.1016/S0896-6273(00)81133-2Vié B, Sablayrolles S, Létienne R, et al. 3-(R)-[3-(2- Methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5- benzoxathiepine Bromhydrate (F 15845) Prevents Ischemia-Induced Heart Remodeling by Reduction of the Intracellular Na+ Overload. J Pharmacol Exp Ther. 2009;330(3):696–703. DOI: 10.1124/JPET.109.153122Vié B, Sablayrolles S, Létienne R, et al. 3-(R)-[3-(2- Methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5- benzoxathiepine Bromhydrate (F 15845) Prevents Ischemia-Induced Heart Remodeling by Reduction of the Intracellular Na+ Overload. J Pharmacol Exp Ther. 2009;330(3):696–703. DOI: 10.1124/JPET.109.153122Vacher B, Pignier C, Létienne R, Verscheure Y, Grand B Le. F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models. Br J Pharmacol. 2009;156(2):214–225. DOI: 10.1111/ J.1476-5381.2008.00062.XVacher B, Pignier C, Létienne R, Verscheure Y, Grand B Le. F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models. Br J Pharmacol. 2009;156(2):214–225. DOI: 10.1111/ J.1476-5381.2008.00062.XPignier C, Rougier JS, Vié B, et al. Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias. Br J Pharmacol. 2010;161(1):79–91. DOI: 10.1111/J.1476-5381.2010.00884.XPignier C, Rougier JS, Vié B, et al. Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias. Br J Pharmacol. 2010;161(1):79–91. DOI: 10.1111/J.1476-5381.2010.00884.XKoltun DO, Parkhill EQ, Elzein E, et al. Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine. Bioorg Med Chem Lett. 2016;26(13):3202–3206. DOI: 10.1016/J.BMCL.2016.03.101Koltun DO, Parkhill EQ, Elzein E, et al. Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine. Bioorg Med Chem Lett. 2016;26(13):3202–3206. DOI: 10.1016/J.BMCL.2016.03.101Koltun DO, Parkhill EQ, Elzein E, et al. Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine. Bioorg Med Chem Lett. 2016;26(13):3207–3211. DOI: 10.1016/J.BMCL.2016.03.096Koltun DO, Parkhill EQ, Elzein E, et al. Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine. Bioorg Med Chem Lett. 2016;26(13):3207–3211. DOI: 10.1016/J.BMCL.2016.03.096Zablocki JA, Elzein E, Li X, et al. Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties. J Med Chem. 2016;59(19):9005–9017. DOI: 10.1021/ACS.JMEDCHEM.6B00939Zablocki JA, Elzein E, Li X, et al. Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties. J Med Chem. 2016;59(19):9005–9017. DOI: 10.1021/ACS.JMEDCHEM.6B00939

The authors declare that there are no conflicts of interest present.