phkineticaФармакокинетика и ФармакодинамикаPharmacokinetics and Pharmacodynamics2587-78362686-8830ООО «Издательство ОКИ»10.37489/2587-7836-2021-4-3-17phkinetica-293Research ArticleАКТУАЛЬНЫЕ ОБЗОРЫCURRENT REVIEWSКардиопротекторные средства с биароматической структурой. Часть 1. Блокаторы кальциевых каналовСardioprotective agents with biaromatic structure. Part 1. Calcium 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 Vladimirovich - PhD Chemical Sci., Leading researcher of the fine organic synthesis laboratory at the drug chemistry department

SPIN code: 8755-7666

Moscow

g.mokrov@gmail.comФГБНУ «Научно-исследовательский институт фармакологии имени В.В. Закусова»РоссияFSBI «Zakusov Institute of Pharmacology»Russian Federation20212102202204317Copyright © 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/293

Сердечно-сосудистые заболевания (ССЗ) широко распространены, являясь ведущей причиной заболеваемости и смертности во всём мире. Лекарства для лечения ССЗ разрабатываются практически с начала 20 века. К настоящему времени создано большое количество кардиопротекторных средств различных классов. Тем не менее потребность в разработке новых эффективных и безопасных лекарств для лечения сердечно-сосудистых заболеваний сохраняется. Данные литературы свидетельствуют о том, что огромное количество кардиопротекторных средств различных поколений и механизмов соответствует единой обобщённой фармакофорной модели, содержащей два ароматических ядра, связанных линейным линкером. В связи с этим мы выдвинули концепцию создания нового поколения кардиопротекторных препаратов с мультитаргетным механизмом действия в рамках указанной фармакофорной модели. Настоящая работа начинает серию обзоров литературы, посвящённых обобщению известных в настоящее время соединений с кардиопротекторными свойствами в ряду соединений, соответствующих фармакофорной модели биароматических соединений, связанных линейным линкером. В представленной первой части описываются блокаторы кальциевых каналов с кардиопротекторным действием. антиаритмики; кардиопротекторы; блокаторы Са2+-каналов; биароматические соединения

Cardiovascular diseases (CVD) are widespread and the leading cause of morbidity and mortality worldwide. Drugs for the treatment of CVD have been developed since the beginning of the 20th century. To date, a large number of cardioprotective agents of various classes have been created. Nevertheless, the need for the development and development of new effective and safe drugs for the treatment of cardiovascular diseases remains. Literature data indicate that a huge number of cardioprotective agents of various generations and mechanisms correspond to a single generalized pharmacophore model containing two aromatic nuclei linked by a linear linker. In this regard, we put forward the concept of creating a new generation of cardioprotective drugs with a multi-targeting mechanism of action within the indicated pharmacophore model. This work begins a series of literature reviews devoted to the generalization of currently known compounds with cardioprotective properties in a series of compounds corresponding to the pharmacophore model of linked biaromatic compounds. The first part presented here describes calcium channel blockers with cardioprotective effects.

антиаритмикикардиопротекторыблокаторы Са2+-каналовбиароматические соединенияantiarrhythmicscardioprotectorsСа2+-channels blockersbiaromatic compoundsReferencesWorld Health Organization: Cardiovascular diseases (CVDs). Published 2021. Accessed October 12, 2021. https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).World Health Organization: Cardiovascular diseases (CVDs). Published 2021. Accessed October 12, 2021. https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).Shaito A, Thuan DTB, Phu HT, et al. Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety. Front Pharmacol. 2020;11:422. DOI: 10.3389/FPHAR.2020.00422.Shaito A, Thuan DTB, Phu HT, et al. Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety. Front Pharmacol. 2020;11:422. DOI: 10.3389/FPHAR.2020.00422.Nánási PP, Pueyo E, Virág L. Editorial: Perspectives of Antiarrhythmic Drug Therapy: Disappointing Past, Current Efforts, and Faint Hopes. Front Pharmacol. 2020;11:1116. DOI:10.3389/FPHAR.2020.01116.Nánási PP, Pueyo E, Virág L. Editorial: Perspectives of Antiarrhythmic Drug Therapy: Disappointing Past, Current Efforts, and Faint Hopes. Front Pharmacol. 2020;11:1116. DOI:10.3389/FPHAR.2020.01116.Davidson SM, Ferdinandy P, Andreadou I, et al. Multitarget Strategies to Reduce Myo-cardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;73(1):89–99. DOI: 10.1016/J.JACC.2018.09.086.Davidson SM, Ferdinandy P, Andreadou I, et al. Multitarget Strategies to Reduce Myo-cardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;73(1):89–99. DOI: 10.1016/J.JACC.2018.09.086.Budillon A, Bruzzese F, Gennaro EDi, Caraglia M. Multiple-Target Drugs: Inhibitors of Heat Shock Protein 90 and of Histone Deacetylase. Curr Drug Targets. 2005;6(3):337–351. DOI: 10.2174/1389450053765905.Budillon A, Bruzzese F, Gennaro EDi, Caraglia M. Multiple-Target Drugs: Inhibitors of Heat Shock Protein 90 and of Histone Deacetylase. Curr Drug Targets. 2005;6(3):337–351. DOI: 10.2174/1389450053765905.Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006;5(12):1034–1049. DOI: 10.1038/nrd2112.Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006;5(12):1034–1049. DOI: 10.1038/nrd2112.Barman M. Proarrhythmic Effects Of Antiarrhythmic Drugs: Case Study Of Flecainide Induced Ventricular Arrhythmias During Treatment Of Atrial Fibrillation. J Atr Fibrillation. 2015;8(4):1091. DOI:10.4022/JAFIB.1091.Barman M. Proarrhythmic Effects Of Antiarrhythmic Drugs: Case Study Of Flecainide Induced Ventricular Arrhythmias During Treatment Of Atrial Fibrillation. J Atr Fibrillation. 2015;8(4):1091. DOI:10.4022/JAFIB.1091.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. DOI: 10.1208/S12248-015-9773-1.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. DOI: 10.1208/S12248-015-9773-1.Song Lv, Zhang Ze-Fu, Hu Liang-Kun, et al. Curcumin, a MultiIon Channel Blocker That Preferentially Blocks Late Na+ Current and Prevents I/R-Induced Arrhythmias. Front Physiol. 2020;11:978. DOI: 10.3389/FPHYS.2020.00978.Song Lv, Zhang Ze-Fu, Hu Liang-Kun, et al. Curcumin, a MultiIon Channel Blocker That Preferentially Blocks Late Na+ Current and Prevents I/R-Induced Arrhythmias. Front Physiol. 2020;11:978. DOI: 10.3389/FPHYS.2020.00978.Hausenloy DJ, Garcia-Dorado D, Bøtker HE, et al. Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc Res. 2017;113(6):564–585. DOI: 10.1093/cvr/cvx049.Hausenloy DJ, Garcia-Dorado D, Bøtker HE, et al. Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc Res. 2017;113(6):564–585. DOI: 10.1093/cvr/cvx049.Der Sarkissian S, Aceros H, Williams PM, Scalabrini C, Borie M, Noiseux N. Heat shock protein 90 inhibition and multi-target approach to maximize cardioprotection in ischaemic injury. Br J Pharmacol. 2020; 177(15):3378–3388. DOI: 10.1111/BPH.15075.Der Sarkissian S, Aceros H, Williams PM, Scalabrini C, Borie M, Noiseux N. Heat shock protein 90 inhibition and multi-target approach to maximize cardioprotection in ischaemic injury. Br J Pharmacol. 2020; 177(15):3378–3388. DOI: 10.1111/BPH.15075.Mirams GR, Cui Y, Sher A, et al. Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovasc Res. 2011;91(1):53–61. DOI:10.1093/cvr/cvr044.Mirams GR, Cui Y, Sher A, et al. Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovasc Res. 2011;91(1):53–61. DOI:10.1093/cvr/cvr044.Martin RL, McDermott JS, Salmen HJ, Palmatier J, Cox BF, Gintant GA. The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block. J Cardiovasc Pharmacol. 2004;43(3):369–379. DOI: 10.1097/00005344-200403000-00007.Martin RL, McDermott JS, Salmen HJ, Palmatier J, Cox BF, Gintant GA. The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block. J Cardiovasc Pharmacol. 2004;43(3):369–379. DOI: 10.1097/00005344-200403000-00007.Kodama I, Kamiya K, Toyama J. Cellular electropharmacology of amiodarone. Cardiovasc Res. 1997;35(1):13–29. DOI: 10.1016/S0008-6363(97)00114-4.Kodama I, Kamiya K, Toyama J. Cellular electropharmacology of amiodarone. Cardiovasc Res. 1997;35(1):13–29. DOI: 10.1016/S0008-6363(97)00114-4.Thollon C, Bedut S, Villeneuve N, et al. Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. Br J Pharmacol. 2007;150(1):37–46. DOI: 10.1038/SJ.BJP.0706940.Thollon C, Bedut S, Villeneuve N, et al. Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. Br J Pharmacol. 2007;150(1):37–46. DOI: 10.1038/SJ.BJP.0706940.Olawi N, Krüger M, Grimm D, Infanger M, Wehland M. Nebivolol in the treatment of arterial hypertension. Basic Clin Pharmacol Toxicol. 2019;125(3):189–201. DOI: 10.1111/BCPT.13248.Olawi N, Krüger M, Grimm D, Infanger M, Wehland M. Nebivolol in the treatment of arterial hypertension. Basic Clin Pharmacol Toxicol. 2019;125(3):189–201. DOI: 10.1111/BCPT.13248.Sakussow jun WW. Über die Wirkung des Papaverins und des Narkotins auf das Herz. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1929;144(5):331–340. DOI: 10.1007/BF01865360.Sakussow jun WW. Über die Wirkung des Papaverins und des Narkotins auf das Herz. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1929;144(5):331–340. DOI: 10.1007/BF01865360.Whipple GH. Papaverine as an Antiarrhythmic Agent. Angiology. 1977;28(11):737–749. DOI: 10.1177/000331977702801102.Whipple GH. Papaverine as an Antiarrhythmic Agent. Angiology. 1977;28(11):737–749. DOI: 10.1177/000331977702801102.Schamroth L, Krikler DM, Garrett C. Immediate effects of intravenous verapamil in cardiac arrhythmias. Br Med J. 1972;1(5801):660–662. DOI: 10.1136/bmj.1.5801.660.Schamroth L, Krikler DM, Garrett C. Immediate effects of intravenous verapamil in cardiac arrhythmias. Br Med J. 1972;1(5801):660–662. DOI: 10.1136/bmj.1.5801.660.Bean BP. Classes of calcium channels in vertebrate cells. Annu Rev Physiol. 1989;51:367–384. DOI: 10.1146/ANNUREV.PH.51.030189.002055.Bean BP. Classes of calcium channels in vertebrate cells. Annu Rev Physiol. 1989;51:367–384. DOI: 10.1146/ANNUREV.PH.51.030189.002055.Szentandrassy N, Nagy D, Hegyi B, Magyar J, Banyasz T, Nanasi PP. Class IV anti-arrhythmic agents: new compounds using an old strategy. Curr Pharm Des. 2015;21(8):977–1010. DOI: 10.2174/1381612820666141029105910.Szentandrassy N, Nagy D, Hegyi B, Magyar J, Banyasz T, Nanasi PP. Class IV anti-arrhythmic agents: new compounds using an old strategy. Curr Pharm Des. 2015;21(8):977–1010. DOI: 10.2174/1381612820666141029105910.Godfraind T. Discovery and Development of Calcium Channel Blockers. Front Pharmacol. 2017;8:286. DOI: 10.3389/FPHAR.2017.00286.Godfraind T. Discovery and Development of Calcium Channel Blockers. Front Pharmacol. 2017;8:286. DOI: 10.3389/FPHAR.2017.00286.Njegic A, Wilson C, Cartwright EJ. Targeting Ca2+ Handling Proteins for the Treatment of Heart Failure and Arrhythmias. Front Physiol. 2020;11:1068. DOI: 10.3389/FPHYS.2020.01068.Njegic A, Wilson C, Cartwright EJ. Targeting Ca2+ Handling Proteins for the Treatment of Heart Failure and Arrhythmias. Front Physiol. 2020;11:1068. DOI: 10.3389/FPHYS.2020.01068.Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med. 2004;116(1):35–43. DOI: 10.1016/J.AMJMED.2003.08.027.Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med. 2004;116(1):35–43. DOI: 10.1016/J.AMJMED.2003.08.027.Fahie S, Cassagnol M. Verapamil. In: In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. StatPearls Publishing; 2021. Accessed October 27, 2021. https://www.ncbi.nlm.nih.gov/books/NBK538495/Fahie S, Cassagnol M. Verapamil. In: In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. StatPearls Publishing; 2021. Accessed October 27, 2021. https://www.ncbi.nlm.nih.gov/books/NBK538495/Fermini B, Ramirez DS, Sun S, et al. L-type calcium channel antagonism – Translation from in vitro to in vivo. J Pharmacol Toxicol Methods. 2017;84:86–92. DOI: 10.1016/J.VASCN.2016.11.002.Fermini B, Ramirez DS, Sun S, et al. L-type calcium channel antagonism – Translation from in vitro to in vivo. J Pharmacol Toxicol Methods. 2017;84:86–92. DOI: 10.1016/J.VASCN.2016.11.002.Wiśniowska B, Mendyk A, Fijorek K, Glinka A, Polak S. Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment. J Appl Toxicol. 2012;32(10):858–866. DOI: 10.1002/JAT.2784.Wiśniowska B, Mendyk A, Fijorek K, Glinka A, Polak S. Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment. J Appl Toxicol. 2012;32(10):858–866. DOI: 10.1002/JAT.2784.Dengel F. US Patent 3261859. Published online 1966.Dengel F. US Patent 3261859. Published online 1966.Balasubramanian B, Imredy JP, Kim D, Penniman J, Lagrutta A, Salata JJ. Optimization of Cav1.2 screening with an automated planar patch clamp platform. J Pharmacol Toxicol Methods. 2009;59(2):62–72. DOI: 10.1016/J.VASCN.2009.02.002.Balasubramanian B, Imredy JP, Kim D, Penniman J, Lagrutta A, Salata JJ. Optimization of Cav1.2 screening with an automated planar patch clamp platform. J Pharmacol Toxicol Methods. 2009;59(2):62–72. DOI: 10.1016/J.VASCN.2009.02.002.Kirchengast M, Hergenröder S. Reperfusion arrhythmias in closedchest rats: the effect of myocardial noradrenaline depletion and Ca2+- antagonism. Clin Exp Pharmacol Physiol. 1991;18(4):217–221. DOI: 10.1111/J.1440-1681.1991.TB01434.xKirchengast M, Hergenröder S. Reperfusion arrhythmias in closedchest rats: the effect of myocardial noradrenaline depletion and Ca2+- antagonism. Clin Exp Pharmacol Physiol. 1991;18(4):217–221. DOI: 10.1111/J.1440-1681.1991.TB01434.xFleckenstein-Grün G. Gallopamil: cardiovascular scope of action of a highly specific calcium antagonist. J Cardiovasc Pharmacol. 1992;20 Suppl 7:S1-S10. DOI: 10.1097/00005344-199200207-00002.Fleckenstein-Grün G. Gallopamil: cardiovascular scope of action of a highly specific calcium antagonist. J Cardiovasc Pharmacol. 1992;20 Suppl 7:S1-S10. DOI: 10.1097/00005344-199200207-00002.Brogden RN, Benfield P. Gallopamil. Drugs. 2012;47(1):93–115. DOI: 10.2165/00003495-199447010-00007.Brogden RN, Benfield P. Gallopamil. Drugs. 2012;47(1):93–115. DOI: 10.2165/00003495-199447010-00007.Zucchi R, Ronca-Testoni S, Yu G, Galbani P, Ronca G, Mariani M. Interaction between gallopamil and cardiac ryanodine receptors. Br J Pharmacol. 1995;114(1):85–92. DOI: 10.1111/j.1476-5381.1995.tb14909.x.Zucchi R, Ronca-Testoni S, Yu G, Galbani P, Ronca G, Mariani M. Interaction between gallopamil and cardiac ryanodine receptors. Br J Pharmacol. 1995;114(1):85–92. DOI: 10.1111/j.1476-5381.1995.tb14909.x.Ramuz H. DE Patent 2460593 A1. Published online 1975. Accessed October 27, 2021. https://worldwide.espacenet.com/patent/search/family/004429892/publication/DE2460593A1?q=DE2460593A1Ramuz H. DE Patent 2460593 A1. Published online 1975. Accessed October 27, 2021. https://worldwide.espacenet.com/patent/search/family/004429892/publication/DE2460593A1?q=DE2460593A1Eigenmann R, Blaber L, Nakamura K, Thorens S, Haeusler G. Tiapamil, a new calcium antagonist. 1. Demonstration of calcium antagonistic activity and related studies. Arzneimittelforschung. 1981;31(9):1393–1401. Accessed October 27, 2021. https://pubmed.ncbi.nlm.nih.gov/7197945/Eigenmann R, Blaber L, Nakamura K, Thorens S, Haeusler G. Tiapamil, a new calcium antagonist. 1. Demonstration of calcium antagonistic activity and related studies. Arzneimittelforschung. 1981;31(9):1393–1401. Accessed October 27, 2021. https://pubmed.ncbi.nlm.nih.gov/7197945/Hoick M, Osterrieder W. Tiapamil. Cardiovasc Drug Rev. 1987;5(1):77– 94. DOI: 10.1111/j.1527-3466.1987.tb00503.x.Hoick M, Osterrieder W. Tiapamil. Cardiovasc Drug Rev. 1987;5(1):77– 94. DOI: 10.1111/j.1527-3466.1987.tb00503.x.Khurmi NS, Robinson CW, O’Hara MJ, Raftery EB. Tiapamil, a new calcium channel blocking agent for the treatment of effort induced chronic stable angina pectoris. Eur J Clin Pharmacol. 1986;30(4):387–392. DOI: 10.1007/BF00607949.Khurmi NS, Robinson CW, O’Hara MJ, Raftery EB. Tiapamil, a new calcium channel blocking agent for the treatment of effort induced chronic stable angina pectoris. Eur J Clin Pharmacol. 1986;30(4):387–392. DOI: 10.1007/BF00607949.Reiffen M, Eberlein W, Mueller P, et al. Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a new class of compounds exerting antiischemic properties. J Med Chem. 1990;33(5):1496–1504. DOI: 10.1021/JM00167A033.Reiffen M, Eberlein W, Mueller P, et al. Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a new class of compounds exerting antiischemic properties. J Med Chem. 1990;33(5):1496–1504. DOI: 10.1021/JM00167A033.Dämmgen J, Kadatz R, Diederen W. Cardiovascular actions of 5,6-dimethoxy-2-(3-[(alpha-(3,4-dimethoxy) phenylethyl)-methylamino] propyl) phthalimidine (AQ-A 39), a specific bradycardic agent. Arzneimittelforschung. 1981;31(4):666–670. Accessed October 27, 2021. https://pubmed.ncbi.nlm.nih.gov/7195712/Dämmgen J, Kadatz R, Diederen W. Cardiovascular actions of 5,6-dimethoxy-2-(3-[(alpha-(3,4-dimethoxy) phenylethyl)-methylamino] propyl) phthalimidine (AQ-A 39), a specific bradycardic agent. Arzneimittelforschung. 1981;31(4):666–670. Accessed October 27, 2021. https://pubmed.ncbi.nlm.nih.gov/7195712/Boucher M, Chassaing C, Chapuy E. Cardiac electrophysiological effects of falipamil in the conscious dog: comparison with alinidine. Eur J Pharmacol. 1996;306(1-3):93–98. DOI: 10.1016/0014-2999(96)00178-1.Boucher M, Chassaing C, Chapuy E. Cardiac electrophysiological effects of falipamil in the conscious dog: comparison with alinidine. Eur J Pharmacol. 1996;306(1-3):93–98. DOI: 10.1016/0014-2999(96)00178-1.Kobinger W, Lillie C. Falipamil (AQ-A 39) and UL-FS 49. Cardiovasc Drug Rev. 1988;6(1):35–53. DOI: 10.1111/j.1527-3466.1988.tb00371.x.Kobinger W, Lillie C. Falipamil (AQ-A 39) and UL-FS 49. Cardiovasc Drug Rev. 1988;6(1):35–53. DOI: 10.1111/j.1527-3466.1988.tb00371.x.Buzby GC. UK Patent 2159815. Published online 1985. Accessed October 27, 2021. https://patentimages.storage.googleapis.com/86/00/ae/8838fccdca5d89/GB2159815A.pdfBuzby GC. UK Patent 2159815. Published online 1985. Accessed October 27, 2021. https://patentimages.storage.googleapis.com/86/00/ae/8838fccdca5d89/GB2159815A.pdfBuzby GC. US Patent 4587360. Published online 1986. Accessed October 27, 2021. https://patentimages.storage.googleapis.com/77/f9/99/8b097c1ad12b48/US4587360.pdfBuzby GC. US Patent 4587360. Published online 1986. Accessed October 27, 2021. https://patentimages.storage.googleapis.com/77/f9/99/8b097c1ad12b48/US4587360.pdfSilver PJ, Fenichel R, Wendt RL. Structural variants of verapamil and W-7 with combined Ca2+ entry blockade/myosin phosphorylation inhibitory mechanisms. J Cardiovasc Pharmacol. 1988;11(3):299–307. DOI: 10.1097/00005344-198803000-00006.Silver PJ, Fenichel R, Wendt RL. Structural variants of verapamil and W-7 with combined Ca2+ entry blockade/myosin phosphorylation inhibitory mechanisms. J Cardiovasc Pharmacol. 1988;11(3):299–307. DOI: 10.1097/00005344-198803000-00006.Gubin J, Chatelain P, Descamps M, et al. US Patent 4957925. Published online 1990.Gubin J, Chatelain P, Descamps M, et al. US Patent 4957925. Published online 1990.Gubin J, Vogelaer H de, Inion H, et al. Novel heterocyclic analogs of the new potent class of calcium entry blockers: 1-[[4-(aminoalkoxy)phenyl] sulfonyl]indolizines. J Med Chem. 1993;36(10):1425–1433. DOI: 10.1021/jm00062a015. https://pubmed.ncbi.nlm.nih.gov/1700816/Gubin J, Vogelaer H de, Inion H, et al. Novel heterocyclic analogs of the new potent class of calcium entry blockers: 1-[[4-(aminoalkoxy)phenyl] sulfonyl]indolizines. J Med Chem. 1993;36(10):1425–1433. DOI: 10.1021/jm00062a015. https://pubmed.ncbi.nlm.nih.gov/1700816/Polster P, Christophe B, Van Damme M, Houlliche A, Chatelain P. SR 33557, a novel calcium entry blocker. I. In vitro isolated tissue studies. J Pharmacol Exp Ther. 1990;255(2):593–599. Accessed October 27, 2021. https://pubmed.ncbi.nlm.nih.gov/1700816/Polster P, Christophe B, Van Damme M, Houlliche A, Chatelain P. SR 33557, a novel calcium entry blocker. I. In vitro isolated tissue studies. J Pharmacol Exp Ther. 1990;255(2):593–599. Accessed October 27, 2021. https://pubmed.ncbi.nlm.nih.gov/1700816/Hodeige D, Chatelain P, Manning A. Fantofarone (SR 33557): Effects on Myocardial Oxygen Consumption and Coronary Blood Flow. Pharmacology. 1994;48(1):49–55. DOI: 10.1159/000139161.Hodeige D, Chatelain P, Manning A. Fantofarone (SR 33557): Effects on Myocardial Oxygen Consumption and Coronary Blood Flow. Pharmacology. 1994;48(1):49–55. DOI: 10.1159/000139161.Glasser SP, Singh SN, Humen DP. Safety and Efficacy of Monotherapy with Fantofarone, a Novel Calcium Channel Antagonist, in Patients with Chronic Stable Angina Pectoris. J Clin Pharmacol. 1997;37(1):53–57. DOI: 10.1177/009127009703700109.Glasser SP, Singh SN, Humen DP. Safety and Efficacy of Monotherapy with Fantofarone, a Novel Calcium Channel Antagonist, in Patients with Chronic Stable Angina Pectoris. J Clin Pharmacol. 1997;37(1):53–57. DOI: 10.1177/009127009703700109.Yamamoto K, Fujita M, Tabashi K, et al. Novel calcium antagonists. Synthesis and struc-ture-activity relationship studies of benzothiazoline derivatives. J Med Chem. 1988;31(5):919–930. DOI: 10.1021/jm00400a006.Yamamoto K, Fujita M, Tabashi K, et al. Novel calcium antagonists. Synthesis and struc-ture-activity relationship studies of benzothiazoline derivatives. J Med Chem. 1988;31(5):919–930. DOI: 10.1021/jm00400a006.Fujita M, Ito S, Ota A, et al. Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl- 3-oxo-2H-1,4-benzothiazines. J Med Chem. 1990;33(7):1898–1905. DOI: 10.1021/jm00169a011.Fujita M, Ito S, Ota A, et al. Synthesis and calcium ion antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl- 3-oxo-2H-1,4-benzothiazines. J Med Chem. 1990;33(7):1898–1905. DOI: 10.1021/jm00169a011.Fukuchi M, Uematsu T, Nagashima S, Nakashima M. Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil. Naunyn Schmiedebergs Arch Pharmacol. 1990;341(6):557–564. DOI: 10.1007/BF00171737.Fukuchi M, Uematsu T, Nagashima S, Nakashima M. Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil. Naunyn Schmiedebergs Arch Pharmacol. 1990;341(6):557–564. DOI: 10.1007/BF00171737.Campiani G, Garofalo A, Fiorini I, et al. Pyrrolo[2,1-c][1,4] benzothiazines: Synthesis, Structure-Activity Relationships, Molecular Modeling Studies, and Cardiovascular Activity. J Med Chem. 1995;38(22):4393–4410. DOI: 10.1021/jm00022a005.Campiani G, Garofalo A, Fiorini I, et al. Pyrrolo[2,1-c][1,4] benzothiazines: Synthesis, Structure-Activity Relationships, Molecular Modeling Studies, and Cardiovascular Activity. J Med Chem. 1995;38(22):4393–4410. DOI: 10.1021/jm00022a005.Yamamori T, Harada H, Sakai K, Iwaki K, Matsunaga K. US Patent 5462936. Published online 1995. Accessed October 28, 2021. https://patentimages.storage.googleapis.com/3d/7f/f6/315ea70560c8d5/US5462936.pdfYamamori T, Harada H, Sakai K, Iwaki K, Matsunaga K. US Patent 5462936. Published online 1995. Accessed October 28, 2021. https://patentimages.storage.googleapis.com/3d/7f/f6/315ea70560c8d5/US5462936.pdfKawakami M, Matsumura S, Shimamura T, et al. Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 2. Hypotensive effects in normotensive and hypertensive rats. J Cardiovasc Pharmacol. 1996;28(5):695–702. DOI: 10.1097/00005344-199611000-00013.Kawakami M, Matsumura S, Shimamura T, et al. Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 2. Hypotensive effects in normotensive and hypertensive rats. J Cardiovasc Pharmacol. 1996;28(5):695–702. DOI: 10.1097/00005344-199611000-00013.Masui M, Funakawa S, Uno O, et al. Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 1. Antinecrotic and antiarrhythmic effects in reperfused rat hearts. J Cardiovasc Pharmacol. 1996;28(4):526–532. DOI: 10.1097/00005344-199610000-00008.Masui M, Funakawa S, Uno O, et al. Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 1. Antinecrotic and antiarrhythmic effects in reperfused rat hearts. J Cardiovasc Pharmacol. 1996;28(4):526–532. DOI: 10.1097/00005344-199610000-00008.Kimoto S, Haruna M, Matsuura E, et al. Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 3. Hypotensive and antimyocardial-stunning effects in dogs. J Cardiovasc Pharmacol. 1997;29(2):180–187. DOI: 10.1097/00005344-199702000-00005.Kimoto S, Haruna M, Matsuura E, et al. Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 3. Hypotensive and antimyocardial-stunning effects in dogs. J Cardiovasc Pharmacol. 1997;29(2):180–187. DOI: 10.1097/00005344-199702000-00005.Mehanna AS, Maher TJ, Grongsaard PP. Design, Synthesis and Calcium Channel Blocking Activity of Diltiazem-Verapamil Hybrid Molecules. Med chem. 2014;4(10):704–703. DOI: 10.4172/2161-0444.1000216.Mehanna AS, Maher TJ, Grongsaard PP. Design, Synthesis and Calcium Channel Blocking Activity of Diltiazem-Verapamil Hybrid Molecules. Med chem. 2014;4(10):704–703. DOI: 10.4172/2161-0444.1000216.Takahara A, Uneyama T, Yoshimoto R, Sugiyama A, Hashimoto K. JP Patent 11228412. Published online 1999.Takahara A, Uneyama T, Yoshimoto R, Sugiyama A, Hashimoto K. JP Patent 11228412. Published online 1999.Takahara A, Sugiyama A, Yoshimoto R, Hashimoto K. AH-1058: a novel cardioselective Ca2+ channel blocker. Cardiovasc Drug Rev. 2001;19(4):279–296. DOI: 10.1111/j.1527-3466.2001.tb00071.x.Takahara A, Sugiyama A, Yoshimoto R, Hashimoto K. AH-1058: a novel cardioselective Ca2+ channel blocker. Cardiovasc Drug Rev. 2001;19(4):279–296. DOI: 10.1111/j.1527-3466.2001.tb00071.x.Branca Q, Jaunin R, Mirki HP, Ramuz H. US Patent 4808605. Published online 1989.Branca Q, Jaunin R, Mirki HP, Ramuz H. US Patent 4808605. Published online 1989.Emanuel K, Mackiewicz U, Pytkowski B, Lewartowski B. Effects of mibefradil, a blocker of T-type Ca2+ channels, in single myocytes and intact muscle of guinea-pig heart. J Physiol Pharmacol. 1998;49(4):577–590. Accessed October 28, 2021. https://pubmed.ncbi.nlm.nih.gov/10069698/Emanuel K, Mackiewicz U, Pytkowski B, Lewartowski B. Effects of mibefradil, a blocker of T-type Ca2+ channels, in single myocytes and intact muscle of guinea-pig heart. J Physiol Pharmacol. 1998;49(4):577–590. Accessed October 28, 2021. https://pubmed.ncbi.nlm.nih.gov/10069698/Leuranguer V, Mangoni ME, Nargeot J, Richard S. Inhibition of T-type and L-type calcium channels by mibefradil: Physiologic and pharmacologic bases of cardiovascular effects. J Cardiovasc Pharmacol. 2001;37(6):649–661. DOI: 10.1097/00005344-200106000-00002.Leuranguer V, Mangoni ME, Nargeot J, Richard S. Inhibition of T-type and L-type calcium channels by mibefradil: Physiologic and pharmacologic bases of cardiovascular effects. J Cardiovasc Pharmacol. 2001;37(6):649–661. DOI: 10.1097/00005344-200106000-00002.Massie BM. Mibefradil, a T-Type Channel-Selective Calcium AntagonistClinical Trials in Chronic Stable Angina Pectoris. Am J Hypertens. 1998;11(4 Pt 3):95S–102S. DOI: 10.1016/S0895-7061(98)00006-5.Massie BM. Mibefradil, a T-Type Channel-Selective Calcium AntagonistClinical Trials in Chronic Stable Angina Pectoris. Am J Hypertens. 1998;11(4 Pt 3):95S–102S. DOI: 10.1016/S0895-7061(98)00006-5.Li M, Hansen JB, Huang L, Keyser BM, Taylor JT. Towards selective antagonists of T-type calcium channels: design, characterization and potential applications of NNC 55-0396. Cardiovasc Drug Rev. 2005;23(2):173–196. DOI: 10.1111/j.1527-3466.2005.tb00164.x.Li M, Hansen JB, Huang L, Keyser BM, Taylor JT. Towards selective antagonists of T-type calcium channels: design, characterization and potential applications of NNC 55-0396. Cardiovasc Drug Rev. 2005;23(2):173–196. DOI: 10.1111/j.1527-3466.2005.tb00164.x.Huang L, Keyser BM, Tagmose TM, et al. NNC 55-0396 [(1S,2S)- 2-(2-(N-[(3-Benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro- 1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: A New Selective Inhibitor of T-Type Calcium Channels. J Pharmacol Exp Ther. 2004;309(1):193–199. DOI: 10.1124/jpet.103.060814.Huang L, Keyser BM, Tagmose TM, et al. NNC 55-0396 [(1S,2S)- 2-(2-(N-[(3-Benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro- 1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: A New Selective Inhibitor of T-Type Calcium Channels. J Pharmacol Exp Ther. 2004;309(1):193–199. DOI: 10.1124/jpet.103.060814.Son YK, Hong DH, Li H, et al. The Ca2+ channel inhibitor NNC 55-0396 inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. J Pharmacol Sci. 2014;125(3):312–319. DOI: 10.1254/jphs.14054fp.Son YK, Hong DH, Li H, et al. The Ca2+ channel inhibitor NNC 55-0396 inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. J Pharmacol Sci. 2014;125(3):312–319. DOI: 10.1254/jphs.14054fp.Matsuda S, Nishikawa H, Fukatsu A, et al. NNC 55-0396, a T-type calcium channel blocker, protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice. J Pharmacol Sci. 2019;140(2):193–196. DOI: 10.1016/J.JPHS.2019.02.002.Matsuda S, Nishikawa H, Fukatsu A, et al. NNC 55-0396, a T-type calcium channel blocker, protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice. J Pharmacol Sci. 2019;140(2):193–196. DOI: 10.1016/J.JPHS.2019.02.002.Hilpert K, Hubler F, Renneberg D. WO Patent 2008132679A1. Published online 2008.Hilpert K, Hubler F, Renneberg D. WO Patent 2008132679A1. Published online 2008.Harsányi K, Korbonits D, Kiss P. Diphenylpropylamine Derivatives. I. N-Substituted 3,3-Diphenylpropylamines. J Med Chem. 1964;7(5):623–625. DOI: 10.1021/jm00335a011.Harsányi K, Korbonits D, Kiss P. Diphenylpropylamine Derivatives. I. N-Substituted 3,3-Diphenylpropylamines. J Med Chem. 1964;7(5):623–625. DOI: 10.1021/jm00335a011.Wiśniowska B, Mendyk A, Fijorek K, Glinka A, Polak S. Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment. J Appl Toxicol. 2012;32(10):858–866. DOI: 10.1002/jat.2784.Wiśniowska B, Mendyk A, Fijorek K, Glinka A, Polak S. Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment. J Appl Toxicol. 2012;32(10):858–866. DOI: 10.1002/jat.2784.Shah RR, Stonier PD. Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty. Ther Adv Drug Saf. 2018;9(8):475–493. DOI: 10.1177/2042098618780854.Shah RR, Stonier PD. Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty. Ther Adv Drug Saf. 2018;9(8):475–493. DOI: 10.1177/2042098618780854.Tripathi O, Schreibmayer W, Tritthart HA. Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study. Br J Pharmacol. 1993;108(4):865–859. DOI: 10.1111/j.1476-5381.1993.tb13479.x.Tripathi O, Schreibmayer W, Tritthart HA. Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study. Br J Pharmacol. 1993;108(4):865–859. DOI: 10.1111/j.1476-5381.1993.tb13479.x.Cho K jin, van der Hoeven D, Hancock JF. Inhibitors of K-Ras Plasma Membrane Localization. Enzymes. 2013;33 Pt A:249–265. DOI: 10.1016/B978-0-12-416749-0.00011-7.Cho K jin, van der Hoeven D, Hancock JF. Inhibitors of K-Ras Plasma Membrane Localization. Enzymes. 2013;33 Pt A:249–265. DOI: 10.1016/B978-0-12-416749-0.00011-7.Bayer B, Mannhold R. Fendiline: a review of its basic pharmacological and clinical properties. Pharmatherapeutica. 1987;5(2):103–136. Accessed October 28, 2021. https://pubmed.ncbi.nlm.nih.gov/3310016/Bayer B, Mannhold R. Fendiline: a review of its basic pharmacological and clinical properties. Pharmatherapeutica. 1987;5(2):103–136. Accessed October 28, 2021. https://pubmed.ncbi.nlm.nih.gov/3310016/Schneider G, Neidhart W, Giller T, Schmid G. "Scaffold-Hopping" by Topological Pharmacophore Search: A Contribution to Virtual Screening. Angew Chem Int Ed Engl. 1999;38(19):2894–2896. Accessed October 28, 2021. https://pubmed.ncbi.nlm.nih.gov/10540384/Schneider G, Neidhart W, Giller T, Schmid G. "Scaffold-Hopping" by Topological Pharmacophore Search: A Contribution to Virtual Screening. Angew Chem Int Ed Engl. 1999;38(19):2894–2896. Accessed October 28, 2021. https://pubmed.ncbi.nlm.nih.gov/10540384/Fagbemi O, Kane KA, McDonald FM, Parratt JR, Rothaul AL. The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats. Br J Pharmacol. 1984;83(1):299–304. DOI: 10.1111/j.1476-5381.1984.tb10146.xFagbemi O, Kane KA, McDonald FM, Parratt JR, Rothaul AL. The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats. Br J Pharmacol. 1984;83(1):299–304. DOI: 10.1111/j.1476-5381.1984.tb10146.xTytgat J, Vereecke J, Carmeliet E. Mechanism of L- and T-type Ca2+ channel blockade by flunarizine in ventricular myocytes of the guineapig. Eur J Pharmacol. 1996;296(2):189–197. DOI: 10.1016/0014-2999(95)00691-5.Tytgat J, Vereecke J, Carmeliet E. Mechanism of L- and T-type Ca2+ channel blockade by flunarizine in ventricular myocytes of the guineapig. Eur J Pharmacol. 1996;296(2):189–197. DOI: 10.1016/0014-2999(95)00691-5.Antoons G, Oros A, Bito V, Sipido KR, Vos MA. Cellular basis for triggered ventricular arrhythmias that occur in the setting of compensated hypertrophy and heart failure: considerations for diagnosis and treatment. J Electrocardiol. 2007;40(6 Suppl):S8-14. DOI: 10.1016/j.jelectrocard.2007.05.022.Antoons G, Oros A, Bito V, Sipido KR, Vos MA. Cellular basis for triggered ventricular arrhythmias that occur in the setting of compensated hypertrophy and heart failure: considerations for diagnosis and treatment. J Electrocardiol. 2007;40(6 Suppl):S8-14. DOI: 10.1016/j.jelectrocard.2007.05.022.Trepakova ES, Dech SJ, Salata JJ. Flunarizine is a highly potent inhibitor of cardiac hERG potassium current. J Cardiovasc Pharmacol. 2006;47(2):211–220. DOI: 10.1097/01.fjc.0000200810.18575.80.Trepakova ES, Dech SJ, Salata JJ. Flunarizine is a highly potent inhibitor of cardiac hERG potassium current. J Cardiovasc Pharmacol. 2006;47(2):211–220. DOI: 10.1097/01.fjc.0000200810.18575.80.Hara H, Toriu N, Shimazawa M. Clinical Potential of Lomerizine, a Ca2+ Channel Blocker as an Anti-Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage. Cardiovasc Drug Rev. 2004;22(3):199–214. DOI: 10.1111/j.1527-3466.2004.tb00141.x.Hara H, Toriu N, Shimazawa M. Clinical Potential of Lomerizine, a Ca2+ Channel Blocker as an Anti-Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage. Cardiovasc Drug Rev. 2004;22(3):199–214. DOI: 10.1111/j.1527-3466.2004.tb00141.x.

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