References

phkinetica

Фармакокинетика и Фармакодинамика

Pharmacokinetics and Pharmacodynamics

2587-78362686-8830

ООО «Издательство ОКИ»

10.37489/2587-7836-2022-4-3-19

phkinetica-338

Research Article

АКТУАЛЬНЫЕ ОБЗОРЫ

CURRENT REVIEWS

Кардиопротекторные средства с биароматической структурой. Часть 4. Блокаторы и модуляторы калиевых hERG-каналов

Сardioprotective agents with biaromatic structure. Part 4. Potassium hERG channels blockers and modulators

https://orcid.org/0000-0003-2617-0334

Мокров

Г. В.

Mokrov

G. V.

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

Москва

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

SPIN code: 8755-7666

Moscow

g.mokrov@gmail.com

ФГБНУ «НИИ фармакологии имени В.В. Закусова»РоссияFSBI «Zakusov Institute of Pharmacology»Russian Federation

2022

18012023

04319

2023

Мокров 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/338

Калиевый канал hERG-подтипа (Kv11.1) является одной из важнейших и одной из наиболее изученных биологических мишеней для создания кардиопротекторных средств. В ряду биароматических соединений описано большое количество как блокаторов, так и активаторов/модуляторов hERG-канала. Вещества с hERG-механизмом используются прежде всего для эффективной регуляции длительности потенциала действия в тканях сердца и контроля интервала QT на электрокардиограмме. В ряду блокаторов hERG наиболее известным препаратом является дофетилид, который используется для поддержания синусового ритма при мерцательной аритмии. В обзоре рассмотрены все известные на сегодняшний день лиганды hERG-канала с биароматической структурой и данные об их биологических свойствах.

The hERG subtype potassium channel (Kv11.1) is one of the most important and one of the most studied biological targets for the creation of cardioprotective agents. A large number of both blockers and activators/modulators of the hERG channel have been described with biaromatic structure. Substances with an hERG-mechanism are used primarily for the effective regulation of the action potential duration in the heart tissues and for the control of the QT interval on the electrocardiogram. Among the hERG blockers, the most well-known drug is dofetilide, which is used to maintain sinus rhythm in atrial fibrillation. The review presents all currently known ligands of the hERG channel with a biaromatic structure and the data on their biological properties.

антиаритмикикардиопротекторыблокаторы hERG-каналовактиваторы/модуляторы hERG-каналовбиароматические соединения

antiarrhythmicscardioprotectorshERG channel blockershERG channel activators/modulatorsbiaromatic compounds

References1

Ravens U, Odening KE. Atrial fibrillation: Therapeutic potential of atrial K+ channel blockers. Pharmacol Ther. 2017;176:13–21. DOI:10.1016/J.PHARMTHERA.2016.10.003.

Ravens U. Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation? Can J Physiol Pharmacol. 2017;95(11):1313–1318. DOI:10.1139/CJPP-2017-0024.

Jeevaratnam K, Chadda KR, Huang CLH, Camm AJ. Cardiac Potassium Channels: Physiological Insights for Targeted Therapy. J Cardiovasc Pharmacol Ther. 2018;23(2):119–129. DOI: 10.1177/1074248417729880.

Nair LA, Grant AO. Emerging class III antiarrhythmic gents: mechanism of action and proarrhythmic potential. Cardiovasc Drugs Ther. 1997;11(2):149–167. DOI: 10.1023/A:1007784814823.

Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov. 2009;8(12):982–1001. DOi: 10.1038/nrd2983.

Мокров Г. В. Кардиопротекторные средства с биароматической структурой. Часть 1. Блокаторы кальциевых каналов. Фармакокинетика и фармакодинамика. 2021;(4):3–17.

Mokrov GV. Сardioprotective agents with biaromatic structure. Part 1. Calcium channel blockers. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2021;(4):3–17. (In Russ). doi: 10.37489/2587-7836-2021-4-3-17.

Мокров Г. В. Кардиопротекторные средства с биароматической структурой. Часть 2. Блокаторы HCN-каналов. Фармакокинетика и фармакодинамика. 2022;(2):3–10.

Mokrov GV. Сardioprotective agents with biaromatic structure. Part 2. HCN channel blockers. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2022;(2):3–10. (In Russ). DOI: 10.37489/2587-7836-2022-2-3-10.

Мокров Г. В. Кардиопротекторные средства с биароматической структурой. Часть 3. Блокаторы натриевых каналов. Фармакокинетика и фармакодинамика. 2022;(3):3–9.

Mokrov GV. Сardioprotective agents with biaromatic structure. Part 3. Sodium channel blockers. Farmakokinetika i farmakodinamika = Pharmacokinetics and pharmacodynamics. 2022;(3):3–9. (In Russ). DOI: 10.37489/2587-7836-2022-3-3-9.

Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. hERG K(+) channels: structure, function, and clinical significance. Physiol Rev. 2012;92(3):1393–1478. DOI: 10.1152/PHYSREV.00036.2011.

Butler A, Helliwell MV, Zhang Y, Hancox JC, Dempsey CE. An Update on the Structure of hERG. Front Pharmacol. 2020;10:1572. DOI: 10.3389/FPHAR.2019.01572.

Lei M, Wu L, Terrar DA, Huang CLH. Modernized classification of cardiac antiarrhythmic drugs. Circulation. 2018;138(17):1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455.

Arrowsmith JE, Cross PE, Thomas GN. GB Patent 8610668. Published online 1987. Accessed October 12, 2021. https://patentimages.storage.googleapis.com/74/ac/e3/672f569217d69e/EP0245997A2.pdf

Cross PE, Arrowsmith JE, Thomas GN, Gwilt M, Burges RA, Higgins AJ. Selective class III antiarrhythmic agents. 1. Bis(arylalkyl)amines. J Med Chem. 1990;33(4):1151–1155. DOI: 10.1021/JM00166A011.

Orvos P, Kohajda Z, Szlovák J, et al. Evaluation of Possible Proarrhythmic Potency: Comparison of the Effect of Dofetilide, Cisapride, Sotalol, Terfenadine, and Verapamil on hERG and Native IKr Currents and on Cardiac Action Potential. Toxicol Sci. 2019;168(2):365–380. DOI: 10.1093/TOXSCI/KFY299.

Wolbrette DL, Hussain S, Maraj I, Naccarelli GV. A Quarter of a Century Later: What is Dofetilide’s Clinical Role Today? J Cardiovasc Pharmacol Ther. 2018;24(1):3–10. DOI: 10.1177/1074248418784288.

Liu H, Ji M, Luo X, et al. New p-Methylsulfonamido Phenylethylamine Analogues as Class III Antiarrhythmic Agents: Design, Synthesis, Biological Assay, and 3D-QSAR Analysis. J Med Chem. 2002;45(14):2953–2969. DOI: 10.1021/JM010574U.

Wang T, Huang ZJ, Dai DZ, Ji M. Comparison of effects of dofetilide derivative V03(CPU228) and dofetilide on coronary occlusion and reperfusion arrhythmia, vascular contractions and proarrhythmic potential of torsade de pointes. Chinese Pharmacol Bull. 2004;20(5):516–520. Accessed October 12, 2021. https://www.researchgate.net/publication/289842760_Comparison_of_effects_of_dofetilide_derivative_V03CPU228_and_dofetilide_on_coronary_occlusion_and_reperfusion_arrhythmia_vascular_contractions_and_proarrhythmic_potential_of_torsade_de_pointes

Huang ZJ, Dai DZ, Li N, Na T, Ji M, Dai Y. Calcium antagonist property of CPU228, a dofetilide derivative, contributes to its low incidence of torsades de pointes in rabbits. Clin Exp Pharmacol Physiol. 2007;34(4):310– 317. DOI: 10.1111/j.1440-1681.2007.04555.x.

Baskin E, Serik C, Wallace A, et al. Effects of new and potent methanesulfonanilide class III antiarrhythmic agents on myocardial refractoriness and contractility in isolated cardiac muscle. J Cardiovasc Pharmacol. 1991;18(3):406–414. DOI: 10.1097/00005344-199109000-00014.

Cross PE, Dickinson RP. US Patent 4806536. Published online 1989.

Rees SA, Curtis MJ. Selective IK blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts. Br J Pharmacol. 1993;108(1):139–145. DOI: 10.1111/j.1476-5381.1993.TB13453.x.

Oinuma H. JP Patent 3927086. Published online 1987.

Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990;96(1):195–215. DOI: 10.1085/jgp.96.1.195.

Adis R&D Profile. E 4031. Drugs R D. 1999;1(4):312–316. DOI: 10.2165/00126839-199901040-00006.

Okada Y, Ogawa S, Sadanaga T, Mitamura H. Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour holter electrocardiography. J Am Coll Cardiol. 1996;27(1):84–89. DOI: 10.1016/0735-1097(95)00424-6.

Kim DI, Kim HY, Kwon LS, et al. Synthesis and biological activity of KCB-328 and its analogues: Novel class III antiarrhythmic agents with little reverse frequency dependence. Bioorg Med Chem Lett. 1999;9(1):85–90. DOI: 10.1016/S0960-894X(98)00689-1.

Rahme MM, Ungab G, Wadhwa M, et al. Electrophysiologic and antiarrhythmic effects of the new class III antiarrhythmic Drug KCB-328 in experimental canine atrial flutter. J Cardiovasc Pharmacol Ther. 2001;6(3):297–306. DOI:10.1177/107424840100600310.

Kanojia RM, Salata JJ, Kauffman J. Synthesis and class III type antiarrhythmic activity of 4-aroyl (and aryl)-1-aralkylpiperazines. Bioorg Med Chem Lett. 2000;10(24):2819–2823. DOI: 10.1016/S0960-894X(00)00581-3.

Hong L, Min J, Ligang L, Song J, Weiyi H, Ruimei L. Synthesis and Antiarrhythmic Activity of Some Methyl sulfonamido phenylethylamino Derivatives. J China Pharmacevtical Univ. 1999;30(1):7–12. Accessed October 12, 2021. http://www.zgykdxxb.cn/jcpuen/article/issue/1999_1

Li P, Sun H feng, Zhou P zheng, et al. Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels. Acta Pharmacol Sin. 2012;33(6):728–736. DOI: 10.1038/aps.2012.41.

Binnig F, Mueller CD, Raschack M, von Philipsborn G. US Patent 4556662. Published online 1985.

Walker BD, Singleton CB, Tie H, et al. Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassiumchannel. Cardiovasc Res. 2000;48(1):44–58. DOI: 10.1016/S0008-6363(00)00155-3.

Kijtawornrat A, Hamlin RL, Hamlin DM. Effects of ambasilide in isolated perfused guinea pig heart. Cardiovasc Toxicol. 2005;5(1):53–62. DOI: 10.1385/CT:5:1:053.

Lubisch W, Binnig F, Philipsborn G von. US Patent 4959373. Published online 1990.

Katakami T, Yokoyama T, Miyamoto M, et al. Synthesis and pharmacological studies of N-substituted 6-[(2-aminoethyl)amino]-1,3- dimethyl-2,4(1H,3H)-pyrimidinediones, novel class III antiarrhythmic agents. J Med Chem. 1992;35(18):3325–3330. DOI: 10.1021/JM00096A003.

Satoh Y, Sugiyama A, Takahara A, Chiba K, Hashimoto K. Electropharmacological and proarrhythmic effects of a class III antiarrhythmic drug nifekalant hydrochloride assessed using the in vivo canine models. J Cardiovasc Pharmacol. 2004;43(5):715–723. DOI: 10.1097/00005344-200405000-00015.

Furutani K, Tsumoto K, Chen IS, et al. Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations. J Gen Physiol. 2019;151(2):214–230. DOI: 10.1085/JGP.201812192.

Hardy JC, Renault C. US Patent 4977166. Published online 1990.

Du L, Li M, You Q, Xia L. A novel structure-based virtual screening model for the hERG channel blockers. Biochem Biophys Res Commun. 2007;355(4):889–894. DOI: 10.1016/J.BBRC.2007.02.068.

Biliczki P, Acsai K, Virág L, et al. Cellular electrophysiological effect of terikalant in the dog heart. Eur J Pharmacol. 2005;510(3):161–166. DOI: 10.1016/J.EJPHAR.2004.12.040.

Escande D, Mestre M, Cavero I, Brugada C, Kirchhof C. RP 58866 and its active enantiomer RP 62719 (terikalant): blockers of the inward rectifier K+ current acting as pure class III antiarrhythmic agents. J Cardiovasc Pharmacol. 1992;20 Suppl 2:s106-13. Accessed October 12, 2021. https://pubmed.ncbi.nlm.nih.gov/1279302/.

Connors SP, Dennis PD, Gill EW, Terrar DA. The synthesis and potassium channel blocking activity of some (4-methanesulfonamidophenoxy) propanolamines as potential class III antiarrhythmic agents. J Med Chem. 2002;34(5):1570–1577. DOI: 10.1021/JM00109A007.

Elliott JM, Selnick HG, Claremon DA, et al. 4-Oxospiro[benzopyran- 2,4’-piperidines] as class III antiarrhythmic agents. Pharmacological studies on 3,4-dihydro-1’-[2-(benzofurazan-5-yl)ethyl]-6-methanesulfonamidospiro[(2H)- 1-benzopyran-2,4’-piperidin]-4-one (L-691,121). J Med Chem. 2002;35(21):3973–3976. DOI: 10.1021/JM00099A028.

Lynch JJ, Wallace AA, Van der Gaag LH, et al. Cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1’-[2- (benzofurazan-5-yl) ethyl]-6-methanesulfonamidospiro [(2H)-1-benzopyran- 2,4’-piperidin]-4-one HCl (L-691,121), a novel class III agent. J Pharmacol Exp Ther. 1993;265(2):720-30.

Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006;440(7083):463–469. DOI: 10.1038/nature04710.

Leishman DJ, Abernathy MM, Wang EB. Revisiting the hERG safety margin after 20 years of routine hERG screening. J Pharmacol Toxicol Methods. 2020;105:106900. DOI: 10.1016/J.VASCN.2020.106900.

Lee K, Park JY, Ryu PD, Kwon LS, Kim HY. IKr channel blockers: novel antiarrhythmic agents. Curr Med Chem Cardiovasc Hematol Agents. 2003;1(3):203–223. DOI: 10.2174/1568016033477414.

Zolotoy AB, Plouvier BP, Beatch GB, Hayes ES, Wall RA, Walker MJA. Physicochemical determinants for drug induced blockade of HERG potassium channels: effect of charge and charge shielding. Curr Med Chem Cardiovasc Hematol Agents. 2003;1(3):225–241. DOI: 10.2174/1568016033477432.

Valentin JP, Hammond T. Safety and secondary pharmacology: Successes, threats, challenges and opportunities. J Pharmacol Toxicol Methods. 2008;58(2):77–87. DOI:10.1016/J.VASCN.2008.05.007.

Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT. Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol. 1999;10(6):836-843. DOI: 10.1111/J.1540-8167.1999.TB00264.X.

Mohammad S, Zhou Z, Gong Q, January CT. Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol Circ Physiol. 1997;42(5):2534–2538. DOI: 10.1152/ AJPHEART.1997.273.5.H2534.

Tanaka H, Takahashi Y, Hamaguchi S, et al. Effect of terfenadine and pentamidine on the HERG channel and its intracellular trafficking: combined analysis with automated voltage clamp and confocal microscopy. Biol Pharm Bull. 2014;37(11):1826–1830. DOI: 10.1248/bpb.b14-00417.

Kang J, Wang L, Cai F, Rampe D. High affinity blockade of the HERG cardiac K(+) channel by the neuroleptic pimozide. Eur J Pharmacol. 2000;392(3):137–140. DOI: 10.1016/S0014-2999(00)00123-0.

Claassen S, Zünkler BJ. Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology. 2005;74(1):31–36. DOI: 10.1159/000083234.

Luo T, Luo A, Liu M, Liu X. Inhibition of the HERG channel by droperidol depends on channel gating and involves the S6 residue F656. Anesth Analg. 2008;106(4):1161–1170. DOI: 10.1213/ANE.0B013E3181684974.

Vigneault P, Pilote S, Patoine D, Simard C, Drolet B. Iloperidone (Fanapt®), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration. Pharmacol Res. 2012;66(1):60–65. DOI: 10.1016/J.PHRS.2012.03.008.

Lee S, Lee HA, Choi SW, Kim SJ, Kim KS. Evaluation of nefazodoneinduced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2016;296:42–53. DOI: 10.1016/J.TAAP.2016.01.015.

Carvalho JFS, Louvel J, Doornbos MLJ, et al. Strategies to reduce HERG K+ channel blockade. Exploring heteroaromaticity and rigidity in novel pyridine analogues of dofetilide. J Med Chem. 2013;56(7):2828–2840. DOI: 10.1021/JM301564F.

Shagufta, Guo D, Klaasse E, et al. Exploring chemical substructures essential for HERG k(+) channel blockade by synthesis and biological evaluation of dofetilide analogues. ChemMedChem. 2009;4(10):1722–1732. DOI: 10.1002/CMDC.200900203.

Vilums M, Overman J, Klaasse E, Scheel O, Brussee J, IJzerman AP. Understanding of molecular substructures that contribute to hERG K+ channel blockade: synthesis and biological evaluation of E-4031 Analogues. ChemMedChem. 2012;7(1):107–113. DOI: 10.1002/CMDC.201100366.

Polak S, Pugsley MK, Stockbridge N, Garnett C, Wiśniowska B. Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates. AAPS J. 2015;17(4):1025–1032. DOI: 10.1208/S12248-015-9773-1.

Lacerda AE, Kuryshev YA, Chen Y, et al. Alfuzosin delays cardiac repolarization by a novel mechanism. J Pharmacol Exp Ther. 2008;324(2):427– 433. DOI: 10.1124/JPET.107.128405.

Kramer J, Obejero-Paz CA, Myatt G, et al. MICE models: superior to the HERG model in predicting Torsade de Pointes. Sci Rep. 2013;3(1):2100. DOI: 10.1038/SREP02100.

Cavero I, Guillon JM, Ballet V, Clements M, Gerbeau JF, Holzgrefe H. Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation. J Pharmacol Toxicol Methods. 2016;81:21–36. DOI: 10.1016/J.VASCN.2016.05.012.

Li Z, Garnett C, Strauss DG. Quantitative Systems Pharmacology Models for a New International Cardiac Safety Regulatory Paradigm: An Overview of the Comprehensive In Vitro Proarrhythmia Assay In Silico Modeling Approach. CPT Pharmacometrics Syst Pharmacol. 2019;8(6):371–379. DOI: 10.1002/PSP4.12423.

Kang J, Chen XL, Wang H, et al. Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol. 2005;67(3):827–836. DOI: 10.1124/MOL.104.006577.

Zhou J, Augelli-Szafran CE, Bradley JA, et al. Novel potent human ether-à-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic Activity. Mol Pharmacol. 2005;68(3):876–884. DOI: 10.1124/MOL.105.014035.

Gerlach AC, Stoehr SJ, Castle NA. Pharmacological removal of human ether-à-go-go-related gene potassium channel inactivation by 3-nitron-( 4-phenoxyphenyl) benzamide (ICA-105574). Mol Pharmacol. 2010;77(1):58–68. DOI: 10.1124/MOL.109.059543.

Meng J, Shi C, Li L, Du Y, Xu Y. Compound ICA-105574 prevents arrhythmias induced by cardiac delayed repolarization. Eur J Pharmacol. 2013;718(1-3):87–97. DOI: 10.1016/J.EJPHAR.2013.09.011.

Potet F, Lorinc AN, Chaigne S, et al. Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related Gene (hERG)-related drug-induced arrhythmias. J Biol Chem. 2012;287(47):39613–39625. DOI: 10.1074/JBC.M112.380162.

Mannikko R, Bridgland-Taylor MH, Pye H, et al. Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K+ channel. Br J Pharmacol. 2015;172(12):3112–3125. DOI: 10.1111/BPH.13115.

Zhang H, Zou B, Yu H, et al. Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel. Proc Natl Acad Sci U S A. 2012;109(29):11866–11871. DOI: 10.1073/PNAS.1205266109.

Yu Z, Van Veldhoven JPD, ’T Hart IME, Kopf AH, Heitman LH, Ijzerman AP. Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel. Eur J Med Chem. 2015;106:50–59. DOI: 10.1016/J.EJMECH.2015.10.032.

Yu Z, Liu J, Veldhoven JPD van, et al. Allosteric Modulation of Kv11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias. Circ Arrhythmia Electrophysiol. 2016;9(4):e003439. DOi: 10.1161/CIRCEP.115.003439.

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