Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Current Targets and Future Directions of Positive Inotropes for Heart Failure

In Press, (this is not the final "Version of Record"). Available online 31 October, 2023
Author(s): Shadreen Fairuz, Chee Wei Ang, Fatima Mraiche and Joo Kheng Goh*
Published on: 31 October, 2023

DOI: 10.2174/0109298673262360231018193823

Price: $95

Abstract

While a congestive heart failure patient will ultimately need an assist device or even a replacement heart as the disease progresses, not every patient is qualified for such advanced therapy. Such patients awaiting better circulatory support benefit from positive inotropes in the meantime as palliative care. These agents are often prescribed in patients with acute decompensated heart failure, with reduced left ventricular ejection fraction and symptoms of organ dysfunction. Although positive inotropes, for example, digoxin, dobutamine, milrinone, levosimendan, etc., are successfully marketed and in use, a lot of their adverse effects, like arrhythmias, hypotension, and even sudden cardiac death, are rather encouraging further research on the development of novel positive inotropes. This review has investigated the molecular mechanisms of some of these adverse effects in terms of the proteins they target, followed by research on newer targets. Studies from 2013-2023 that have reported new small molecules with positive inotropic effects have been revisited in order to determine the progress made so far in drug discovery.

[1]
Groenewegen, A.; Rutten, F.H.; Mosterd, A.; Hoes, A.W. Epidemiology of heart failure. Eur. J. Heart Fail., 2020, 22(8), 1342-1356.
[http://dx.doi.org/10.1002/ejhf.1858] [PMID: 32483830]
[2]
Kannel, W.B. Incidence and epidemiology of heart failure. Heart Fail. Rev., 2000, 5(2), 167-173.
[http://dx.doi.org/10.1023/A:1009884820941] [PMID: 16228142]
[3]
Savarese, G.; Becher, P.M.; Lund, L.H.; Seferovic, P.; Rosano, G.M.C.; Coats, A.J.S. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc. Res., 2023, 118(17), 3272-3287.
[http://dx.doi.org/10.1093/cvr/cvac013] [PMID: 35150240]
[4]
Bozkurt, B.; Coats, A.J.S.; Tsutsui, H.; Abdelhamid, M.; Adamopoulos, S.; Albert, N.; Anker, S.D.; Atherton, J.; Böhm, M.; Butler, J.; Drazner, M.H.; Felker, G.M.; Filippatos, G.; Fonarow, G.C.; Fiuzat, M.; Gomez-Mesa, J.E.; Heidenreich, P.; Imamura, T.; Januzzi, J.; Jankowska, E.A.; Khazanie, P.; Kinugawa, K.; Lam, C.S.P.; Matsue, Y.; Metra, M.; Ohtani, T.; Francesco Piepoli, M.; Ponikowski, P.; Rosano, G.M.C.; Sakata, Y.; SeferoviĆ, P.; Starling, R.C.; Teerlink, J.R.; Vardeny, O.; Yamamoto, K.; Yancy, C.; Zhang, J.; Zieroth, S. Universal definition and classification of heart failure: a report of the heart failure society of America, heart failure association of the European society of cardiology, Japanese heart failure society and writing committee of the universal definition of heart failure. J. Card. Fail., 2021, 27(4), 387-413.
[http://dx.doi.org/10.1016/j.cardfail.2021.01.022] [PMID: 33663906]
[5]
Francis, G.S.; Tang, W.H. Pathophysiology of congestive heart failure. Rev. Cardiovasc. Med., 2003, 4(S2)(Suppl. 2), S14-S20.
[PMID: 12776009]
[6]
Link, M.G.; Yan, G.X.; Kowey, P.R. Evaluation of toxicity for heart failure therapeutics: studying effects on the QT interval. Circ. Heart Fail., 2010, 3(4), 547-555.
[http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.917781] [PMID: 20647490]
[7]
Malik, A.; Brito, D.; Vaqar, S.; Chhabra, L. Congestive heart failure. Stat Pearls; Stat Pearls Publishing, 2022.
[8]
Kosaraju, A.; Goyal, A.; Grigorova, Y.; Makaryus, A.N. Left ventricular ejection fraction. Stat Pearls; Stat Pearls Publishing. 2017.
[9]
Francis, G.S.; Bartos, J.A.; Adatya, S. Inotropes. J. Am. Coll. Cardiol., 2014, 63(20), 2069-2078.
[http://dx.doi.org/10.1016/j.jacc.2014.01.016] [PMID: 24530672]
[10]
McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; Cleland, J.G.F.; Coats, A.J.S.; Crespo-Leiro, M.G.; Farmakis, D.; Gilard, M.; Heymans, S.; Hoes, A.W.; Jaarsma, T.; Jankowska, E.A.; Lainscak, M.; Lam, C.S.P.; Lyon, A.R.; McMurray, J.J.V.; Mebazaa, A.; Mindham, R.; Muneretto, C.; Francesco Piepoli, M.; Price, S.; Rosano, G.M.C.; Ruschitzka, F.; Kathrine Skibelund, A. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. J. Heart Fail., 2022, 24(1), 4-131.
[http://dx.doi.org/10.1002/ejhf.2333] [PMID: 35083827]
[11]
Tariq, S.; Aronow, W. Use of inotropic agents in treatment of systolic heart failure. Int. J. Mol. Sci., 2015, 16(12), 29060-29068.
[http://dx.doi.org/10.3390/ijms161226147] [PMID: 26690127]
[12]
Pinnell, J.; Turner, S.; Howell, S. Cardiac muscle physiology. Contin. Educ. Anaesth. Crit. Care Pain, 2007, 7(3), 85-88.
[http://dx.doi.org/10.1093/bjaceaccp/mkm013]
[13]
Eisner, D.A.; Caldwell, J.L.; Kistamás, K.; Trafford, A.W. Calcium and excitation-contraction coupling in the heart. Circ. Res., 2017, 121(2), 181-195.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.310230] [PMID: 28684623]
[14]
Barry, S.P.; Townsend, P.A. What causes a broken heart--molecular insights into heart failure. Int. Rev. Cell Mol. Biol., 2010, 284, 113-179.
[http://dx.doi.org/10.1016/S1937-6448(10)84003-1] [PMID: 20875630]
[15]
Ziff, O.J.; Kotecha, D. Digoxin: The good and the bad. Trends Cardiovasc. Med., 2016, 26(7), 585-595.
[http://dx.doi.org/10.1016/j.tcm.2016.03.011] [PMID: 27156593]
[16]
Ahmad, T.; Miller, P.E.; McCullough, M.; Desai, N.R.; Riello, R.; Psotka, M.; Böhm, M.; Allen, L.A.; Teerlink, J.R.; Rosano, G.M.C.; Lindenfeld, J. Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials. Eur. J. Heart Fail., 2019, 21(9), 1064-1078.
[http://dx.doi.org/10.1002/ejhf.1557] [PMID: 31407860]
[17]
Colucci, W.S.; Wright, R.F.; Braunwald, E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 1. N. Engl. J. Med., 1986, 314(5), 290-299.
[http://dx.doi.org/10.1056/NEJM198601303140506] [PMID: 2867470]
[18]
Nieminen, M.S.; Fruhwald, S.; Heunks, L.M.; Suominen, P.K.; Gordon, A.C.; Kivikko, M.; Pollesello, P. Levosimendan: current data, clinical use and future development. Heart Lung Vessel., 2013, 5(4), 227-245.
[PMID: 24364017]
[19]
Morth, J.P.; Pedersen, B.P.; Toustrup-Jensen, M.S.; Sørensen, T.L.M.; Petersen, J.; Andersen, J.P.; Vilsen, B.; Nissen, P. Crystal structure of the sodium–potassium pump. Nature, 2007, 450(7172), 1043-1049.
[http://dx.doi.org/10.1038/nature06419] [PMID: 18075585]
[20]
Fuller, W.; Tulloch, L.B.; Shattock, M.J.; Calaghan, S.C.; Howie, J.; Wypijewski, K.J. Regulation of the cardiac sodium pump. Cell. Mol. Life Sci., 2013, 70(8), 1357-1380.
[http://dx.doi.org/10.1007/s00018-012-1134-y] [PMID: 22955490]
[21]
Wasserstrom, J.A.; Aistrup, G.L. Digitalis: new actions for an old drug. Am. J. Physiol. Heart Circ. Physiol., 2005, 289(5), H1781-H1793.
[http://dx.doi.org/10.1152/ajpheart.00707.2004] [PMID: 16219807]
[22]
Askari, A. The sodium pump and digitalis drugs: Dogmas and fallacies. Pharmacol. Res. Perspect., 2019, 7(4), e00505.
[http://dx.doi.org/10.1002/prp2.505] [PMID: 31360524]
[23]
Habeck, M.; Haviv, H.; Katz, A.; Kapri-Pardes, E.; Ayciriex, S.; Shevchenko, A.; Ogawa, H.; Toyoshima, C.; Karlish, S.J.D. Stimulation, inhibition, or stabilization of Na,K-ATPase caused by specific lipid interactions at distinct sites. J. Biol. Chem., 2015, 290(8), 4829-4842.
[http://dx.doi.org/10.1074/jbc.M114.611384] [PMID: 25533463]
[24]
El-Seedi, H.R.; Khalifa, S.A.M.; Taher, E.A.; Farag, M.A.; Saeed, A.; Gamal, M.; Hegazy, M.E.F.; Youssef, D.; Musharraf, S.G.; Alajlani, M.M.; Xiao, J.; Efferth, T. Cardenolides: Insights from chemical structure and pharmacological utility. Pharmacol. Res., 2019, 141, 123-175.
[http://dx.doi.org/10.1016/j.phrs.2018.12.015] [PMID: 30579976]
[25]
Motiejunaite, J.; Amar, L.; Vidal-Petiot, E. Adrenergic receptors and cardiovascular effects of catecholamines. Ann Endocrinol (Paris), 2021, 82(3-4), 193-197.
[26]
Najafi, A.; Sequeira, V.; Kuster, D.W.D.; van der Velden, J. β-adrenergic receptor signalling and its functional consequences in the diseased heart. Eur. J. Clin. Invest., 2016, 46(4), 362-374.
[http://dx.doi.org/10.1111/eci.12598] [PMID: 26842371]
[27]
Ciccarelli, M.; Sorriento, D.; Coscioni, E.; Iaccarino, G.; Santulli, G. Chapter 11 - Adrenergic receptors. Endocrinology of the Heart in Health and Disease. 2017, 285-315.
[28]
Arrigo, M.; Mebazaa, A. Understanding the differences among inotropes. Intensive Care Med., 2015, 41(5), 912-915.
[http://dx.doi.org/10.1007/s00134-015-3659-7] [PMID: 25605474]
[29]
Bobin, P.; Belacel-Ouari, M.; Bedioune, I.; Zhang, L.; Leroy, J.; Leblais, V.; Fischmeister, R.; Vandecasteele, G. Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective. Arch. Cardiovasc. Dis., 2016, 109(6-7), 431-443.
[http://dx.doi.org/10.1016/j.acvd.2016.02.004] [PMID: 27184830]
[30]
Kim, G.E.; Kass, D.A. Cardiac phosphodiesterases and their modulation for treating heart disease. Handb. Exp. Pharmacol., 2016, 243, 249-269.
[http://dx.doi.org/10.1007/164_2016_82] [PMID: 27787716]
[31]
Preedy, M.E.J. Cardiac cyclic nucleotide phosphodiesterases: roles and therapeutic potential in heart failure. Cardiovasc. Drugs Ther., 2020, 34(3), 401-417.
[http://dx.doi.org/10.1007/s10557-020-06959-1] [PMID: 32172427]
[32]
Mayhew, D.J.; Palmer, K. Inotropes. Anaesth. Intensive Care Med., 2015, 16(10), 508-512.
[http://dx.doi.org/10.1016/j.mpaic.2015.07.006]
[33]
Gilotra, N.A.; DeVore, A.D.; Povsic, T.J.; Hays, A.G.; Hahn, V.S.; Agunbiade, T.A.; DeLong, A.; Satlin, A.; Chen, R.; Davis, R.; Kass, D.A. Acute hemodynamic effects and tolerability of phosphodiesterase-1 inhibition with ITI-214 in human systolic heart failure. Circ. Heart Fail., 2021, 14(9), e008236.
[http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008236] [PMID: 34461742]
[34]
Hoffman, T.M. Phosphodiesterase inhibitors. Heart Failure in the Child and Young Adult; Elsevier, 2018, pp. 517-522.
[http://dx.doi.org/10.1016/B978-0-12-802393-8.00040-5]
[35]
Kamel, R.; Leroy, J.; Vandecasteele, G.; Fischmeister, R. Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. Nat. Rev. Cardiol., 2023, 20(2), 90-108.
[http://dx.doi.org/10.1038/s41569-022-00756-z] [PMID: 36050457]
[36]
Movsesian, M.; Ahmad, F.; Hirsch, E. Functions of PDE3 isoforms in cardiac muscle. J. Cardiovasc. Dev. Dis., 2018, 5(1), 10.
[http://dx.doi.org/10.3390/jcdd5010010] [PMID: 29415428]
[37]
Li, M.X.; Hwang, P.M. Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs. Gene, 2015, 571(2), 153-166.
[http://dx.doi.org/10.1016/j.gene.2015.07.074] [PMID: 26232335]
[38]
Kalyva, A.; Parthenakis, F.I.; Marketou, M.E.; Kontaraki, J.E.; Vardas, P.E. Biochemical characterisation of Troponin C mutations causing hypertrophic and dilated cardiomyopathies. J. Muscle Res. Cell Motil., 2014, 35(2), 161-178.
[http://dx.doi.org/10.1007/s10974-014-9382-0] [PMID: 24744096]
[39]
Grześk, G.; Wołowiec, Ł.; Rogowicz, D.; Gilewski, W.; Kowalkowska, M.; Banach, J.; Hertmanowski, W.; Dobosiewicz, M. The importance of pharmacokinetics, pharmacodynamic and repetitive use of levosimendan. Biomed. Pharmacother., 2022, 153, 113391.
[http://dx.doi.org/10.1016/j.biopha.2022.113391] [PMID: 36076524]
[40]
Gonano, L.A.; Petroff, M.V. Subcellular mechanisms underlying digitalis-induced arrhythmias: role of calcium/calmodulin-dependent kinase II (CaMKII) in the transition from an inotropic to an arrhythmogenic effect. Heart Lung Circ., 2014, 23(12), 1118-1124.
[http://dx.doi.org/10.1016/j.hlc.2014.07.074] [PMID: 25201479]
[41]
Tse, G. Mechanisms of cardiac arrhythmias. J. Arrhythm., 2016, 32(2), 75-81.
[http://dx.doi.org/10.1016/j.joa.2015.11.003] [PMID: 27092186]
[42]
Zhang, J.; Simpson, P.C.; Jensen, B.C. Cardiac α1A-adrenergic receptors: emerging protective roles in cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol., 2021, 320(2), H725-H733.
[http://dx.doi.org/10.1152/ajpheart.00621.2020] [PMID: 33275531]
[43]
Belletti, A.; Castro, M.L.; Silvetti, S.; Greco, T.; Biondi-Zoccai, G.; Pasin, L.; Zangrillo, A.; Landoni, G. The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br. J. Anaesth., 2015, 115(5), 656-675.
[http://dx.doi.org/10.1093/bja/aev284] [PMID: 26475799]
[44]
Pollesello, P.; Papp, Z.; Papp, J.G. Calcium sensitizers: What have we learned over the last 25years? Int. J. Cardiol., 2016, 203, 543-548.
[http://dx.doi.org/10.1016/j.ijcard.2015.10.240] [PMID: 26580334]
[45]
Alsulami, K.; Marston, S. Small molecules acting on myofilaments as treatments for heart and skeletal muscle diseases. Int. J. Mol. Sci., 2020, 21(24), 9599.
[http://dx.doi.org/10.3390/ijms21249599] [PMID: 33339418]
[46]
Meissner, G. The structural basis of ryanodine receptor ion channel function. J. Gen. Physiol., 2017, 149(12), 1065-1089.
[http://dx.doi.org/10.1085/jgp.201711878] [PMID: 29122978]
[47]
Maxwell, J.T.; Domeier, T.L.; Blatter, L.A. Dantrolene prevents arrhythmogenic Ca 2+ release in heart failure. Am. J. Physiol. Heart Circ. Physiol., 2012, 302(4), H953-H963.
[http://dx.doi.org/10.1152/ajpheart.00936.2011] [PMID: 22180651]
[48]
Fischer, T.H.; Maier, L.S.; Sossalla, S. The ryanodine receptor leak: how a tattered receptor plunges the failing heart into crisis. Heart Fail. Rev., 2013, 18(4), 475-483.
[http://dx.doi.org/10.1007/s10741-012-9339-6] [PMID: 22932727]
[49]
Hasenfuss, G.; Teerlink, J.R. Cardiac inotropes: current agents and future directions. Eur. Heart J., 2011, 32(15), 1838-1845.
[http://dx.doi.org/10.1093/eurheartj/ehr026] [PMID: 21388993]
[50]
Marx, S.O.; Marks, A.R. Dysfunctional ryanodine receptors in the heart: New insights into complex cardiovascular diseases. J. Mol. Cell. Cardiol., 2013, 58, 225-231.
[http://dx.doi.org/10.1016/j.yjmcc.2013.03.005] [PMID: 23507255]
[51]
Petzhold, D.; Lossie, J.; Keller, S.; Werner, S.; Haase, H.; Morano, I. Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity. Cardiovasc. Res., 2011, 90(3), 513-520.
[http://dx.doi.org/10.1093/cvr/cvr026] [PMID: 21262909]
[52]
Planelles-Herrero, V.J.; Hartman, J.J.; Robert-Paganin, J.; Malik, F.I.; Houdusse, A. Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil. Nat. Commun., 2017, 8(1), 190.
[http://dx.doi.org/10.1038/s41467-017-00176-5] [PMID: 28775348]
[53]
Kaplinsky, E.; Mallarkey, G. Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil. Drugs Context, 2018, 7, 1-10.
[http://dx.doi.org/10.7573/dic.212518] [PMID: 29707029]
[54]
Metra, M.; Pagnesi, M.; Claggett, B.L.; Díaz, R.; Felker, G.M.; McMurray, J.J.V.; Solomon, S.D.; Bonderman, D.; Fang, J.C.; Fonseca, C.; Goncalvesova, E.; Howlett, J.G.; Li, J.; O’Meara, E.; Miao, Z.M.; Abbasi, S.A.; Heitner, S.B.; Kupfer, S.; Malik, F.I.; Teerlink, J.R. Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial. Eur. Heart J., 2022, 43(48), 5006-5016.
[http://dx.doi.org/10.1093/eurheartj/ehac293] [PMID: 35675469]
[55]
Teerlink, J.R.; Diaz, R.; Felker, G.M.; McMurray, J.J.V.; Metra, M.; Solomon, S.D.; Adams, K.F.; Anand, I.; Arias-Mendoza, A.; Biering-Sørensen, T.; Böhm, M.; Bonderman, D.; Cleland, J.G.F.; Corbalan, R.; Crespo-Leiro, M.G.; Dahlström, U.; Echeverria, L.E.; Fang, J.C.; Filippatos, G.; Fonseca, C.; Goncalvesova, E.; Goudev, A.R.; Howlett, J.G.; Lanfear, D.E.; Li, J.; Lund, M.; Macdonald, P.; Mareev, V.; Momomura, S.; O’Meara, E.; Parkhomenko, A.; Ponikowski, P.; Ramires, F.J.A.; Serpytis, P.; Sliwa, K.; Spinar, J.; Suter, T.M.; Tomcsanyi, J.; Vandekerckhove, H.; Vinereanu, D.; Voors, A.A.; Yilmaz, M.B.; Zannad, F.; Sharpsten, L.; Legg, J.C.; Varin, C.; Honarpour, N.; Abbasi, S.A.; Malik, F.I.; Kurtz, C.E. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N. Engl. J. Med., 2021, 384(2), 105-116.
[http://dx.doi.org/10.1056/NEJMoa2025797] [PMID: 33185990]
[56]
Sikkel, M.B.; Hayward, C.; MacLeod, K.T.; Harding, S.E.; Lyon, A.R. SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope. Br. J. Pharmacol., 2014, 171(1), 38-54.
[http://dx.doi.org/10.1111/bph.12472] [PMID: 24138023]
[57]
Zhihao, L.; Jingyu, N.; Lan, L.; Michael, S.; Rui, G.; Xiyun, B.; Xiaozhi, L.; Guanwei, F. SERCA2a: a key protein in the Ca2+ cycle of the heart failure. Heart Fail. Rev., 2020, 25(3), 523-535.
[http://dx.doi.org/10.1007/s10741-019-09873-3] [PMID: 31701344]
[58]
Park, W.J.; Oh, J.G. SERCA2a: a prime target for modulation of cardiac contractility during heart failure. BMB Rep., 2013, 46(5), 237-243.
[http://dx.doi.org/10.5483/BMBRep.2013.46.5.077] [PMID: 23710633]
[59]
Korpela, H.; Järveläinen, N.; Siimes, S.; Lampela, J.; Airaksinen, J.; Valli, K.; Turunen, M.; Pajula, J.; Nurro, J.; Ylä-Herttuala, S. Gene therapy for ischaemic heart disease and heart failure. J. Intern. Med., 2021, 290(3), 567-582.
[http://dx.doi.org/10.1111/joim.13308] [PMID: 34033164]
[60]
Arcaro, A.; Lembo, G.; Tocchetti, C.G. Nitroxyl (HNO) for treatment of acute heart failure. Curr. Heart Fail. Rep., 2014, 11(3), 227-235.
[http://dx.doi.org/10.1007/s11897-014-0210-z] [PMID: 24980211]
[61]
Maack, C.; Eschenhagen, T.; Hamdani, N.; Heinzel, F.R.; Lyon, A.R.; Manstein, D.J.; Metzger, J.; Papp, Z.; Tocchetti, C.G.; Yilmaz, M.B.; Anker, S.D.; Balligand, J.L.; Bauersachs, J.; Brutsaert, D.; Carrier, L.; Chlopicki, S.; Cleland, J.G.; de Boer, R.A.; Dietl, A.; Fischmeister, R.; Harjola, V.P.; Heymans, S.; Hilfiker-Kleiner, D.; Holzmeister, J.; de Keulenaer, G.; Limongelli, G.; Linke, W.A.; Lund, L.H.; Masip, J.; Metra, M.; Mueller, C.; Pieske, B.; Ponikowski, P.; Ristić, A.; Ruschitzka, F.; Seferović, P.M.; Skouri, H.; Zimmermann, W.H.; Mebazaa, A. Treatments targeting inotropy. Eur. Heart J., 2019, 40(44), 3626-3644.
[http://dx.doi.org/10.1093/eurheartj/ehy600] [PMID: 30295807]
[62]
Ferrandi, M.; Barassi, P.; Tadini-Buoninsegni, F.; Bartolommei, G.; Molinari, I.; Tripodi, M.G.; Reina, C.; Moncelli, M.R.; Bianchi, G.; Ferrari, P. Istaroxime stimulates SERCA2A and accelerates calcium cycling in heart failure by relieving phospholamban inhibition. Br. J. Pharmacol., 2013, 169(8), 1849-1861.
[http://dx.doi.org/10.1111/bph.12278] [PMID: 23763364]
[63]
Avvisato, R.; Jankauskas, S.S.; Santulli, G. Istaroxime and beyond: New therapeutic strategies to specifically activate SERCA and treat heart failure. J. Pharmacol. Exp. Ther., 2023, 384(1), 227-230.
[http://dx.doi.org/10.1124/jpet.122.001446] [PMID: 36581352]
[64]
Figueroa-Valverde, L.; Diaz-Cedillo, F.; Lopez-Ramos, M.; Garcia-Cervera, E.; Quijano, K.; Cordoba, J. Changes induced by estradiol-ethylenediamine derivative on perfusion pressure and coronary resistance in isolated rat heart: L-type calcium channel. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2011, 155(1), 27-32.
[http://dx.doi.org/10.5507/bp.2011.018] [PMID: 21475374]
[65]
Templeton, J.F.; Kumar, V.P.S.; Cote, D.; Bose, D.; Elliott, D.; Kim, R.S.; LaBella, F.S. Progesterone derivatives that bind to the digitalis receptor: synthesis of 14.beta.-hydroxyprogesterone: a novel steroid with positive inotropic activity. J. Med. Chem., 1987, 30(8), 1502-1505.
[http://dx.doi.org/10.1021/jm00391a038] [PMID: 3612692]
[66]
López-Ramos, M.; Figueroa-Valverde, L.; Herrera-Meza, S.; Rosas-Nexticapa, M.; Díaz-Cedillo, F.; García-Cervera, E.; Pool-Gómez, E.; Cahuich-Carrillo, R. Design and synthesis of a new steroid-macrocyclic derivative with biological activity. J. Chem. Biol., 2017, 10(2), 69-84.
[http://dx.doi.org/10.1007/s12154-017-0165-0] [PMID: 28405241]
[67]
Lauro, F.V.; Francisco, D.C.; Elodia, G.C.; Eduardo, P.G.; Marcela, R.N.; Lenin, H.H.; Betty, S.A. Design and synthesis of new dihydrotestosterone derivative with positive inotropic activity. Steroids, 2015, 95, 39-50.
[http://dx.doi.org/10.1016/j.steroids.2014.12.026] [PMID: 25578737]
[68]
Rocchetti, M.; Besana, A.; Mostacciuolo, G.; Micheletti, R.; Ferrari, P.; Sarkozi, S.; Szegedi, C.; Jona, I.; Zaza, A. Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride]. J. Pharmacol. Exp. Ther., 2005, 313(1), 207-215.
[http://dx.doi.org/10.1124/jpet.104.077933] [PMID: 15576469]
[69]
Metra, M.; Chioncel, O.; Cotter, G.; Davison, B.; Filippatos, G.; Mebazaa, A.; Novosadova, M.; Ponikowski, P.; Simmons, P.; Soffer, J.; Simonson, S. Safety and efficacy of istaroxime in patients with acute heart failure-related pre-cardiogenic shock – a multicentre, randomized, double-blind, placebo-controlled, parallel group study ( SEISMIC ). Eur. J. Heart Fail., 2022, 24(10), 1967-1977.
[http://dx.doi.org/10.1002/ejhf.2629] [PMID: 35867804]
[70]
Arici, M.; Ferrandi, M.; Barassi, P.; Hsu, S.C.; Torre, E.; Luraghi, A.; Ronchi, C.; Chang, G.J.; Peri, F.; Ferrari, P.; Bianchi, G.; Rocchetti, M.; Zaza, A. Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function. J. Pharmacol. Exp. Ther., 2023, 384(1), 231-244.
[http://dx.doi.org/10.1124/jpet.122.001335] [PMID: 36153005]
[71]
Luraghi, A.; Ferrandi, M.; Barassi, P.; Arici, M.; Hsu, S.C.; Torre, E.; Ronchi, C.; Romerio, A.; Chang, G.J.; Ferrari, P.; Bianchi, G.; Zaza, A.; Rocchetti, M.; Peri, F. Highly selective SERCA2a activators: Preclinical development of a congeneric group of first-in-class drug leads against heart failure. J. Med. Chem., 2022, 65(10), 7324-7333.
[http://dx.doi.org/10.1021/acs.jmedchem.2c00347] [PMID: 35580334]
[72]
Meng, Q.; Yau, L.F.; Lu, J.G.; Wu, Z.Z.; Zhang, B.X.; Wang, J.R.; Jiang, Z.H. Chemical profiling and cytotoxicity assay of bufadienolides in toad venom and toad skin. J. Ethnopharmacol., 2016, 187, 74-82.
[http://dx.doi.org/10.1016/j.jep.2016.03.062] [PMID: 27063985]
[73]
Liang, G.; Chung, T.; Guo, J.; Zhang, R.; Xü, W.; Tzen, J.T.C.; Jiang, R. Novel cinobufagin oxime ether derivatives as potential Na+/K+-ATPase inhibitors: Synthesis, biological screening and molecular docking. Chem. Res. Chin. Univ., 2017, 33(3), 378-383.
[http://dx.doi.org/10.1007/s40242-017-6487-1]
[74]
Tang, H.J.; Ruan, L.J.; Tian, H.Y.; Liang, G.P.; Ye, W.C.; Hughes, E.; Esmann, M.; Fedosova, N.U.; Chung, T.Y.; Tzen, J.T.C.; Jiang, R.W.; Middleton, D.A. Novel stereoselective bufadienolides reveal new insights into the requirements for Na+, K+-ATPase inhibition by cardiotonic steroids. Sci. Rep., 2016, 6(1), 29155.
[http://dx.doi.org/10.1038/srep29155] [PMID: 27377465]
[75]
Wink, M.; Roberts, M.F. Alkaloids: biochemistry, ecology, and medicinal applications; Plenum Press, 1998.
[76]
Wei, J.W.; Liao, J.F.; Chuang, C.Y.; Chen, C.F.; Han, P.W. Cardiovascular effects of matrine isolated from the Chinese herb Shan-dou-gen. Proc. Natl. Sci. Counc. Repub. China B, 1985, 9(3), 215-219.
[PMID: 4070509]
[77]
Boido, V.; Ercoli, M.; Tonelli, M.; Novelli, F.; Tasso, B.; Sparatore, F.; Cichero, E.; Fossa, P.; Dorigo, P.; Froldi, G. New arylsparteine derivatives as positive inotropic drugs. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 588-599.
[http://dx.doi.org/10.1080/14756366.2017.1279156] [PMID: 28133984]
[78]
Li, W. C. Application of 2,5 -dihydroxymethyl-3,6-dimethyl pyrazine and its derivates in pharmacy. US8158630B2, 2012.
[79]
Liu, Z.; Li, W.; Wen, H.M.; Bian, H.M.; Zhang, J.; Chen, L.; Chen, L.; Yang, K.D. Synthesis, biological evaluation, and pharmacokinetic study of novel liguzinediol prodrugs. Molecules, 2013, 18(4), 4561-4572.
[http://dx.doi.org/10.3390/molecules18044561] [PMID: 23599014]
[80]
Zhang, J.; Li, W.; Wen, H.M.; Zhu, H.H.; Wang, T.L.; Cheng, D.; Yang, K.D.; Chen, Y.Q. Synthesis and biological evaluation of liguzinediol mono- and dual ester prodrugs as promising inotropic agents. Molecules, 2014, 19(11), 18057-18072.
[http://dx.doi.org/10.3390/molecules191118057] [PMID: 25379643]
[81]
Wu, Y.; Sun, L.P.; Ma, L.X.; Che, J.; Song, M.X.; Cui, X.; Piao, H.R. Synthesis and biological evaluation of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted benzylpiperazine moieties as positive inotropic agents. Chem. Biol. Drug Des., 2013, 81(5), 591-599.
[http://dx.doi.org/10.1111/cbdd.12101] [PMID: 23279930]
[82]
Ma, L.X.; Cui, B.R.; Wu, Y.; Liu, J.C.; Cui, X.; Liu, L.P.; Piao, H.R. Synthesis and positive inotropic evaluation of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted piperazine moieties. Bioorg. Med. Chem. Lett., 2014, 24(7), 1737-1741.
[http://dx.doi.org/10.1016/j.bmcl.2014.02.040] [PMID: 24636107]
[83]
Liu, X.K.; Ma, L.X.; Wei, Z.Y.; Cui, X.; Zhan, S.; Yin, X.M.; Piao, H.R. Synthesis and positive inotropic activity of [1,2,4]triazolo[4, 3-a] quinoxaline derivatives bearing substituted benzylpiperazine and benzoylpiperazine moieties. Molecules, 2017, 22(2), 273.
[http://dx.doi.org/10.3390/molecules22020273] [PMID: 28208674]
[84]
Humphrey, J.M.; Movsesian, M.; am Ende, C.W.; Becker, S.L.; Chappie, T.A.; Jenkinson, S.; Liras, J.L.; Liras, S.; Orozco, C.; Pandit, J.; Vajdos, F.F.; Vandeput, F.; Yang, E.; Menniti, F.S. Discovery of potent and selective periphery-restricted quinazoline inhibitors of the cyclic nucleotide phosphodiesterase PDE1. J. Med. Chem., 2018, 61(10), 4635-4640.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00374] [PMID: 29718668]
[85]
Hashimoto, T.; Kim, G.E.; Tunin, R.S.; Adesiyun, T.; Hsu, S.; Nakagawa, R.; Zhu, G.; O’Brien, J.J.; Hendrick, J.P.; Davis, R.E.; Yao, W.; Beard, D.; Hoxie, H.R.; Wennogle, L.P.; Lee, D.I.; Kass, D.A. Acute enhancement of cardiac function by phosphodiesterase type 1 inhibition: translational study in the dog and rabbit. Circulation, 2018, 138(18), 1974-1987.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.030490] [PMID: 30030415]
[86]
Muller, G.K.; Song, J.; Jani, V.; Wu, Y.; Liu, T.; Jeffreys, W.P.D.; O’Rourke, B.; Anderson, M.E.; Kass, D.A. PDE1 inhibition modulates Cav1. 2 channel to stimulate cardiomyocyte contraction. Circ. Res., 2021, 129(9), 872-886.
[http://dx.doi.org/10.1161/CIRCRESAHA.121.319828] [PMID: 34521216]
[87]
Humphrey, J.M.; Yang, E.; am Ende, C.W.; Arnold, E.P.; Head, J.L.; Jenkinson, S.; Lebel, L.A.; Liras, S.; Pandit, J.; Samas, B.; Vajdos, F.; Simons, S.P.; Evdokimov, A.; Mansoura, M.; Menniti, F.S. Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1. MedChemComm, 2014, 5(9), 1290-1296.
[http://dx.doi.org/10.1039/C4MD00113C]
[88]
Cleland, J.G.F.; Teerlink, J.R.; Senior, R.; Nifontov, E.M.; Mc Murray, J.J.V.; Lang, C.C.; Tsyrlin, V.A.; Greenberg, B.H.; Mayet, J.; Francis, D.P.; Shaburishvili, T.; Monaghan, M.; Saltzberg, M.; Neyses, L.; Wasserman, S.M.; Lee, J.H.; Saikali, K.G.; Clarke, C.P.; Goldman, J.H.; Wolff, A.A.; Malik, F.I. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet, 2011, 378(9792), 676-683.
[http://dx.doi.org/10.1016/S0140-6736(11)61126-4] [PMID: 21856481]
[89]
Manickam, M.; Jalani, H.B.; Pillaiyar, T.; Sharma, N.; Boggu, P.R.; Venkateswararao, E.; Lee, Y.J.; Jeon, E.S.; Jung, S.H. Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure. Eur. J. Med. Chem., 2017, 134, 379-391.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.005] [PMID: 28432943]
[90]
Manickam, M.; Jalani, H.B.; Pillaiyar, T.; Boggu, P.R.; Sharma, N.; Venkateswararao, E.; Lee, Y.J.; Jeon, E.S.; Son, M.J.; Woo, S.H.; Jung, S.H. Design and synthesis of sulfonamidophenylethylureas as novel cardiac myosin activator. Eur. J. Med. Chem., 2018, 143, 1869-1887.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.077] [PMID: 29224951]
[91]
Manickam, M.; Pillaiyar, T.; Namasivayam, V.; Boggu, P.R.; Sharma, N.; Jalani, H.B.; Venkateswararao, E.; Lee, Y.J.; Jeon, E.S.; Son, M.J.; Woo, S.H.; Jung, S.H. Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator. Bioorg. Med. Chem., 2019, 27(18), 4110-4123.
[http://dx.doi.org/10.1016/j.bmc.2019.07.041] [PMID: 31378598]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy