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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

The Design of Multi-target Drugs to Treat Cardiovascular Diseases: Two (or more) Birds on One Stone

Author(s): Lucas Caruso, Nathalia Fonseca Nadur, Marina Brandão da Fonseca, Larissa de Almeida Peixoto Ferreira, Renata Barbosa Lacerda, Cedric Stephan Graebin and Arthur Eugen Kümmerle*

Volume 22, Issue 5, 2022

Published on: 16 February, 2022

Page: [366 - 394] Pages: 29

DOI: 10.2174/1568026622666220201151248

Price: $65

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Abstract

Cardiovascular diseases (CVDs) comprise a group of diseases and disorders of the heart and blood vessels, which together are the number one cause of death worldwide, being associated with multiple genetic and modifiable risk factors, and that may directly arise from different etiologies. For a long time, the search for cardiovascular drugs was based on the old paradigm “one compound - one target”, aiming to obtain a highly potent and selective molecule with only one desired molecular target. Although historically successful in the last decades, this approach ignores the multiple causes and the multifactorial nature of CVDs. Thus, over time, treatment strategies for cardiovascular diseases have changed, and, currently, pharmacological therapies for CVD are mainly based on the association of two or more drugs to control symptoms and reduce cardiovascular death. In this context, the development of multitarget drugs, i.e., compounds having the ability to act simultaneously at multiple sites, is an attractive and relevant strategy that can be even more advantageous to achieve predictable pharmacokinetic and pharmacodynamics correlations as well as better patient compliance. In this review, we aim to highlight the efforts and rational pharmacological bases for the design of some promising multitargeted compounds to treat important cardiovascular diseases like heart failure, atherosclerosis, acute myocardial infarction, pulmonary arterial hypertension, and arrhythmia.

Keywords: Cardiovascular diseases, Multi-target Drugs, Molecular hybridization, Heart failure, Atherosclerosis, Acute myocardial infarction, Pulmonary arterial hypertension, Arrhythmia.

Graphical Abstract

[1]
World Health Organization. Cardiovascular diseases (CV), 2017.
[2]
Roth, G.A.; Johnson, C.; Abajobir, A.; Abd-Allah, F.; Abera, S.F.; Abyu, G.; Ahmed, M.; Aksut, B.; Alam, T.; Alam, K.; Alla, F.; Alvis-Guzman, N.; Amrock, S.; Ansari, H.; Ärnlöv, J.; Asayesh, H.; Atey, T.M.; Avila-Burgos, L.; Awasthi, A.; Banerjee, A.; Barac, A.; Bärnighausen, T.; Barregard, L.; Bedi, N.; Belay Ketema, E.; Bennett, D.; Berhe, G.; Bhutta, Z.; Bitew, S.; Carapetis, J.; Carrero, J.J.; Malta, D.C.; Castañeda-Orjuela, C.A.; Castillo-Rivas, J.; Catalá-López, F.; Choi, J-Y.; Christensen, H.; Cirillo, M.; Cooper, L., Jr; Criqui, M.; Cundiff, D.; Damasceno, A.; Dandona, L.; Dandona, R.; Davletov, K.; Dharmaratne, S.; Dorairaj, P.; Dubey, M.; Ehrenkranz, R.; El Sayed Zaki, M.; Faraon, E.J.A.; Esteghamati, A.; Farid, T.; Farvid, M.; Feigin, V.; Ding, E.L.; Fowkes, G.; Gebrehiwot, T.; Gillum, R.; Gold, A.; Gona, P.; Gupta, R.; Habtewold, T.D.; Hafezi-Nejad, N.; Hailu, T.; Hailu, G.B.; Hankey, G.; Hassen, H.Y.; Abate, K.H.; Havmoeller, R.; Hay, S.I.; Horino, M.; Hotez, P.J.; Jacobsen, K.; James, S.; Javanbakht, M.; Jeemon, P.; John, D.; Jonas, J.; Kalkonde, Y.; Karimkhani, C.; Kasaeian, A.; Khader, Y.; Khan, A.; Khang, Y-H.; Khera, S.; Khoja, A.T.; Khubchandani, J.; Kim, D.; Kolte, D.; Kosen, S.; Krohn, K.J.; Kumar, G.A.; Kwan, G.F.; Lal, D.K.; Larsson, A.; Linn, S.; Lopez, A.; Lotufo, P.A.; El Razek, H.M.A.; Malekzadeh, R.; Mazidi, M.; Meier, T.; Meles, K.G.; Mensah, G.; Meretoja, A.; Mezgebe, H.; Miller, T.; Mirrakhimov, E.; Mohammed, S.; Moran, A.E.; Musa, K.I.; Narula, J.; Neal, B.; Ngalesoni, F.; Nguyen, G.; Obermeyer, C.M.; Owolabi, M.; Patton, G.; Pedro, J.; Qato, D.; Qorbani, M.; Rahimi, K.; Rai, R.K.; Rawaf, S.; Ribeiro, A.; Safiri, S.; Salomon, J.A.; Santos, I.; Santric Milicevic, M.; Sartorius, B.; Schutte, A.; Sepanlou, S.; Shaikh, M.A.; Shin, M-J.; Shishehbor, M.; Shore, H.; Silva, D.A.S.; Sobngwi, E.; Stranges, S.; Swaminathan, S.; Tabarés-Seisdedos, R.; Tadele Atnafu, N.; Tesfay, F.; Thakur, J.S.; Thrift, A.; Topor-Madry, R.; Truelsen, T.; Tyrovolas, S.; Ukwaja, K.N.; Uthman, O.; Vasankari, T.; Vlassov, V.; Vollset, S.E.; Wakayo, T.; Watkins, D.; Weintraub, R.; Werdecker, A.; Westerman, R.; Wiysonge, C.S.; Wolfe, C.; Workicho, A.; Xu, G.; Yano, Y.; Yip, P.; Yonemoto, N.; Younis, M.; Yu, C.; Vos, T.; Naghavi, M.; Murray, C. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol., 2017, 70(1), 1-25.
[http://dx.doi.org/10.1016/j.jacc.2017.04.052 ] [PMID: 28527533]
[3]
Kaptoge, S.; Pennells, L.; De Bacquer, D.; Cooney, M.T.; Kavousi, M.; Stevens, G.; Riley, L.M.; Savin, S.; Khan, T.; Altay, S.; Amouyel, P.; Assmann, G.; Bell, S.; Ben-Shlomo, Y.; Berkman, L.; Beulens, J.W.; Björkelund, C.; Blaha, M.; Blazer, D.G.; Bolton, T.; Bonita Beaglehole, R.; Brenner, H.; Brunner, E.J.; Casiglia, E.; Chamnan, P.; Choi, Y-H.; Chowdry, R.; Coady, S.; Crespo, C.J.; Cushman, M.; Dagenais, G.R.; D’Agostino Sr, R.B.; Daimon, M.; Davidson, K.W.; Engström, G.; Ford, I.; Gallacher, J.; Gansevoort, R.T.; Gaziano, T.A.; Giampaoli, S.; Grandits, G.; Grimsgaard, S.; Grobbee, D.E.; Gudnason, V.; Guo, Q.; Tolonen, H.; Humphries, S.; Iso, H.; Jukema, J.W.; Kauhanen, J.; Kengne, A.P.; Khalili, D.; Koenig, W.; Kromhout, D.; Krumholz, H.; Lam, T.; Laughlin, G.; Marín Ibañez, A.; Meade, T.W.; Moons, K.G.M.; Nietert, P.J.; Ninomiya, T.; Nordestgaard, B.G.; O’Donnell, C.; Palmieri, L.; Patel, A.; Perel, P.; Price, J.F.; Providencia, R.; Ridker, P.M.; Rodriguez, B.; Rosengren, A.; Roussel, R.; Sakurai, M.; Salomaa, V.; Sato, S.; Schöttker, B.; Shara, N.; Shaw, J.E.; Shin, H-C.; Simons, L.A.; Sofianopoulou, E.; Sundström, J.; Völzke, H.; Wallace, R.B.; Wareham, N.J.; Willeit, P.; Wood, D.; Wood, A.; Zhao, D.; Woodward, M.; Danaei, G.; Roth, G.; Mendis, S.; Onuma, O.; Varghese, C.; Ezzati, M.; Graham, I.; Jackson, R.; Danesh, J.; Di Angelantonio, E. World health organization cardiovascular disease risk charts: Revised models to estimate risk in 21 global regions. Lancet Glob. Health, 2019, 7(10), e1332-e1345.
[http://dx.doi.org/10.1016/S2214-109X(19)30318-3 ] [PMID: 31488387]
[4]
GBD 2017 causes of death collaborators. global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: A systematic analysis for the global burden of disease study 2017. Lancet Lond. Engl., 2018, 392, 1736-1788.
[http://dx.doi.org/10.1016/S0140-6736(18)32203-7]
[5]
Rosengren, A.; Smyth, A.; Rangarajan, S.; Ramasundarahettige, C.; Bangdiwala, S.I.; AlHabib, K.F.; Avezum, A.; Bengtsson Boström, K.; Chifamba, J.; Gulec, S.; Gupta, R.; Igumbor, E.U.; Iqbal, R.; Ismail, N.; Joseph, P.; Kaur, M.; Khatib, R.; Kruger, I.M.; Lamelas, P.; Lanas, F.; Lear, S.A.; Li, W.; Wang, C.; Quiang, D.; Wang, Y.; Lopez-Jaramillo, P.; Mohammadifard, N.; Mohan, V.; Mony, P.K.; Poirier, P.; Srilatha, S.; Szuba, A.; Teo, K.; Wielgosz, A.; Yeates, K.E.; Yusoff, K.; Yusuf, R.; Yusufali, A.H.; Attaei, M.W.; McKee, M.; Yusuf, S. Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: the Prospective Urban Rural Epidemiologic (PURE) study. Lancet Glob. Health, 2019, 7(6), e748-e760.
[http://dx.doi.org/10.1016/S2214-109X(19)30045-2 ] [PMID: 31028013]
[6]
Lee, G.; Carrington, M. Tackling heart disease and poverty. Nurs. Health Sci., 2007, 9(4), 290-294.
[http://dx.doi.org/10.1111/j.1442-2018.2007.00363.x ] [PMID: 17958679]
[7]
Callander, E.J.; Schofield, D.J. The risk of falling into poverty after developing heart disease: A survival analysis. BMC Public Health, 2016, 16, 570.
[http://dx.doi.org/10.1186/s12889-016-3240-5 ] [PMID: 27417645]
[8]
Lopez, A.D.; Adair, T. Is the long-term decline in cardiovascular-disease mortality in high-income countries over? Evidence from national vital statistics. Int. J. Epidemiol., 2019, 48(6), 1815-1823.
[http://dx.doi.org/10.1093/ije/dyz143 ] [PMID: 31378814]
[9]
Espinoza-Fonseca, L.M. The benefits of the multi-target approach in drug design and discovery. Bioorg. Med. Chem., 2006, 14(4), 896-897.
[http://dx.doi.org/10.1016/j.bmc.2005.09.011 ] [PMID: 16203151]
[10]
Yuan, Y.; Pei, J.; Lai, L. LigBuilder V3: A Multi-target de novo drug design approach. Front Chem., 2020, 8, 142.
[http://dx.doi.org/10.3389/fchem.2020.00142 ] [PMID: 32181242]
[11]
Mills, E.J.; Nachega, J.B.; Bangsberg, D.R.; Singh, S.; Rachlis, B.; Wu, P.; Wilson, K.; Buchan, I.; Gill, C.J.; Cooper, C. Adherence to HAART: A systematic review of developed and developing nation patient-reported barriers and facilitators. PLoS Med., 2006, 3(11), e438.
[http://dx.doi.org/10.1371/journal.pmed.0030438 ] [PMID: 17121449]
[12]
Korcsmáros, T.; Szalay, M.S.; Böde, C.; Kovács, I.A.; Csermely, P. How to design multi-target drugs. Expert Opin. Drug Discov., 2007, 2(6), 799-808.
[http://dx.doi.org/10.1517/17460441.2.6.799 ] [PMID: 23488998]
[13]
Ramsay, R.R.; Popovic-Nikolic, M.R.; Nikolic, K.; Uliassi, E.; Bolognesi, M.L. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med., 2018, 7(1), 3.
[http://dx.doi.org/10.1186/s40169-017-0181-2 ] [PMID: 29340951]
[14]
Libby, P.; Buring, J.E.; Badimon, L.; Hansson, G.K.; Deanfield, J.; Bittencourt, M.S.; Tokgözoğlu, L.; Lewis, E.F. Atherosclerosis. Nat. Rev. Dis. Primers, 2019, 5(1), 56.
[http://dx.doi.org/10.1038/s41572-019-0106-z ] [PMID: 31420554]
[15]
Weber, C.; Noels, H. Atherosclerosis: Current pathogenesis and therapeutic options. Nat. Med., 2011, 17(11), 1410-1422.
[http://dx.doi.org/10.1038/nm.2538 ] [PMID: 22064431]
[16]
Solanki, A.; Bhatt, L.K.; Johnston, T.P. Evolving targets for the treatment of atherosclerosis. Pharmacol. Ther., 2018, 187, 1-12.
[http://dx.doi.org/10.1016/j.pharmthera.2018.02.002 ] [PMID: 29414673]
[17]
Lu, H.; Daugherty, A. Atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 2015, 35(3), 485-491.
[http://dx.doi.org/10.1161/ATVBAHA.115.305380 ] [PMID: 25717174]
[18]
Li, B.; Li, W.; Li, X.; Zhou, H. Inflammation: A novel therapeutic target/direction in atherosclerosis. Curr. Pharm. Des., 2017, 23(8), 1216-1227.
[http://dx.doi.org/10.2174/1381612822666161230142931 ] [PMID: 28034355]
[19]
Wang, B.; Wu, L.; Chen, J.; Dong, L.; Chen, C.; Wen, Z.; Hu, J.; Fleming, I.; Wang, D.W. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct. Target. Ther., 2021, 6(1), 94.
[http://dx.doi.org/10.1038/s41392-020-00443-w ] [PMID: 33637672]
[20]
Nakamura, H.; Murayama, T. Role of sphingolipids in arachidonic acid metabolism. J. Pharmacol. Sci., 2014, 124(3), 307-312.
[http://dx.doi.org/10.1254/jphs.13R18CP ] [PMID: 24599139]
[21]
Elzahhar, P.A.; Alaaeddine, R.; Ibrahim, T.M.; Nassra, R.; Ismail, A.; Chua, B.S.K.; Frkic, R.L.; Bruning, J.B.; Wallner, N.; Knape, T.; von Knethen, A.; Labib, H.; El-Yazbi, A.F.; Belal, A.S.F. Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones. Eur. J. Med. Chem., 2019, 167, 562-582.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.034 ] [PMID: 30818268]
[22]
Bergqvist, F.; Morgenstern, R.; Jakobsson, P-J. A review on mPGES-1 inhibitors: From preclinical studies to clinical applications. Prostaglandins Other Lipid Mediat., 2020, 147, 106383.
[http://dx.doi.org/10.1016/j.prostaglandins.2019.106383 ] [PMID: 31698145]
[23]
Gao, X.; Gong, H.; Men, P.; Zhou, L.; Ye, D. Design, synthesis, and biological evaluation of novel dual inhibitors of secretory phospholipase A2 and sphingomyelin synthase. Chin. J. Chem., 2013, 31, 1164-1170.
[http://dx.doi.org/10.1002/cjoc.201300079]
[24]
Pirat, C.; Farce, A.; Lebègue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting peroxisome proliferator-activated receptors (PPARs): Development of modulators. J. Med. Chem., 2012, 55(9), 4027-4061.
[http://dx.doi.org/10.1021/jm101360s ] [PMID: 22260081]
[25]
Jamkhande, P.G.; Chandak, P.G.; Dhawale, S.C.; Barde, S.R.; Tidke, P.S.; Sakhare, R.S. Therapeutic approaches to drug targets in atherosclerosis. Saudi Pharm. J., 2014, 22(3), 179-190.
[http://dx.doi.org/10.1016/j.jsps.2013.04.005 ] [PMID: 25061401]
[26]
Hopkins, P.N. Molecular biology of atherosclerosis. Physiol. Rev., 2013, 93(3), 1317-1542.
[http://dx.doi.org/10.1152/physrev.00004.2012 ] [PMID: 23899566]
[27]
Kourounakis, A.P.; Bavavea, E. New applications of squalene synthase inhibitors: Membrane cholesterol as a therapeutic target. Arch. Pharm. (Weinheim), 2020, 353(9), e2000085.
[http://dx.doi.org/10.1002/ardp.202000085 ] [PMID: 32557793]
[28]
Kühne, H.; Obst-Sander, U.; Kuhn, B.; Conte, A.; Ceccarelli, S.M.; Neidhart, W.; Rudolph, M.G.; Ottaviani, G.; Gasser, R.; So, S-S.; Li, S.; Zhang, X.; Gao, L.; Myers, M. Design and synthesis of selective, dual fatty acid binding protein 4 and 5 inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(20), 5092-5097.
[http://dx.doi.org/10.1016/j.bmcl.2016.08.071 ] [PMID: 27658368]
[29]
Gong, H.; Zhou, L.; Ye, D.; Gao, X.; Li, Y.; Qi, X.; Chu, Y. Novel dual inhibitors of secretory phospholipase A2 and sphingomyelin synthase: Design, synthesis and evaluation. Lett. Drug Des. Discov., 2016, 13, 1025-1032.
[http://dx.doi.org/10.2174/1570180813666160805155116]
[30]
Kourounakis, A.P.; Matralis, A.N.; Nikitakis, A. Design of more potent squalene synthase inhibitors with multiple activities. Bioorg. Med. Chem., 2010, 18(21), 7402-7412.
[http://dx.doi.org/10.1016/j.bmc.2010.09.008 ] [PMID: 20888243]
[31]
Matralis, A.N.; Katselou, M.G.; Nikitakis, A.; Kourounakis, A.P. Novel benzoxazine and benzothiazine derivatives as multifunctional antihyperlipidemic agents. J. Med. Chem., 2011, 54(15), 5583-5591.
[http://dx.doi.org/10.1021/jm200763k ] [PMID: 21702499]
[32]
Matralis, A.N.; Kourounakis, A.P. Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: Exploiting phenothiazine’s strong antioxidant activity. J. Med. Chem., 2014, 57(6), 2568-2581.
[http://dx.doi.org/10.1021/jm401842e ] [PMID: 24568631]
[33]
Matralis, A.N.; Kourounakis, A.P. Optimizing the pharmacological profile of new bifunctional antihyperlipidemic/antioxidant morpholine derivatives. ACS Med. Chem. Lett., 2018, 10(1), 98-104.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00469 ] [PMID: 30655954]
[34]
Banoglu, E.; Çelikoğlu, E.; Völker, S.; Olgaç, A.; Gerstmeier, J.; Garscha, U.; Çalışkan, B.; Schubert, U.S.; Carotti, A.; Macchiarulo, A.; Werz, O. 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP). Eur. J. Med. Chem., 2016, 113, 1-10.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.027 ] [PMID: 26922224]
[35]
Garscha, U.; Voelker, S.; Pace, S.; Gerstmeier, J.; Emini, B.; Liening, S.; Rossi, A.; Weinigel, C.; Rummler, S.; Schubert, U.S.; Scriba, G.K.E.; Çelikoğlu, E.; Çalışkan, B.; Banoglu, E.; Sautebin, L.; Werz, O. BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly. Biochem. Pharmacol., 2016, 119, 17-26.
[http://dx.doi.org/10.1016/j.bcp.2016.08.023 ] [PMID: 27592027]
[36]
Gürses, T.; Olğaç, A.; Garscha, U.; Gür Maz, T.; Bal, N.B.; Uludağ, O.; Çalışkan, B.; Schubert, U.S.; Werz, O.; Banoglu, E. Simple heteroaryl modifications in the 4,5-diarylisoxazol-3-carboxylic acid scaffold favorably modulates the activity as dual mPGES-1/5-LO inhibitors with in vivo efficacy. Bioorg. Chem., 2021, 112, 104861.
[http://dx.doi.org/10.1016/j.bioorg.2021.104861 ] [PMID: 33826984]
[37]
He, Y.; Dou, H.; Gao, D.; Wang, T.; Zhang, M.; Wang, H.; Li, Y. Identification of new dual FABP4/5 inhibitors based on a naphthalene-1-sulfonamide FABP4 inhibitor. Bioorg. Med. Chem., 2019, 27(19), 115015.
[http://dx.doi.org/10.1016/j.bmc.2019.07.031 ] [PMID: 31420256]
[38]
Gao, D-D.; Dou, H-X.; Su, H-X.; Zhang, M-M.; Wang, T.; Liu, Q-F.; Cai, H-Y.; Ding, H-P.; Yang, Z.; Zhu, W-L.; Xu, Y-C.; Wang, H-Y.; Li, Y-X. From hit to lead: Structure-based discovery of naphthalene-1-sulfonamide derivatives as potent and selective inhibitors of fatty acid binding protein 4. Eur. J. Med. Chem., 2018, 154, 44-59.
[http://dx.doi.org/10.1016/j.ejmech.2018.05.007 ] [PMID: 29775936]
[39]
Buscató, E.; Blöcher, R.; Lamers, C.; Klingler, F-M.; Hahn, S.; Steinhilber, D.; Schubert-Zsilavecz, M.; Proschak, E. Design and synthesis of dual modulators of soluble epoxide hydrolase and peroxisome proliferator-activated receptors. J. Med. Chem., 2012, 55(23), 10771-10775.
[http://dx.doi.org/10.1021/jm301194c]
[40]
Anderson, J.L.; Morrow, D.A. Acute myocardial infarction. N. Engl. J. Med., 2017, 376(21), 2053-2064.
[http://dx.doi.org/10.1056/NEJMra1606915 ] [PMID: 28538121]
[41]
Thygesen, K.; Alpert, J.S.; Jaffe, A.S.; Simoons, M.L.; Chaitman, B.R.; White, H.D.; Thygesen, K.; Alpert, J.S.; White, H.D.; Jaffe, A.S.; Katus, H.A.; Apple, F.S.; Lindahl, B.; Morrow, D.A.; Chaitman, B.R.; Clemmensen, P.M.; Johanson, P.; Hod, H.; Underwood, R.; Bax, J.J.; Bonow, J.J.; Pinto, F.; Gibbons, R.J.; Fox, K.A.; Atar, D.; Newby, L.K.; Galvani, M.; Hamm, C.W.; Uretsky, B.F.; Steg, P.G.; Wijns, W.; Bassand, J.P.; Menasche, P.; Ravkilde, J.; Ohman, E.M.; Antman, E.M.; Wallentin, L.C.; Armstrong, P.W.; Simoons, M.L.; Januzzi, J.L.; Nieminen, M.S.; Gheorghiade, M.; Filippatos, G.; Luepker, R.V.; Fortmann, S.P.; Rosamond, W.D.; Levy, D.; Wood, D.; Smith, S.C.; Hu, D.; Lopez-Sendon, J.L.; Robertson, R.M.; Weaver, D.; Tendera, M.; Bove, A.A.; Parkhomenko, A.N.; Vasilieva, E.J.; Mendis, S.; Bax, J.J.; Baumgartner, H.; Ceconi, C.; Dean, V.; Deaton, C.; Fagard, R.; Funck-Brentano, C.; Hasdai, D.; Hoes, A.; Kirchhof, P.; Knuuti, J.; Kolh, P.; McDonagh, T.; Moulin, C.; Popescu, B.A.; Reiner, Z.; Sechtem, U.; Sirnes, P.A.; Tendera, M.; Torbicki, A.; Vahanian, A.; Windecker, S.; Morais, J.; Aguiar, C.; Almahmeed, W.; Arnar, D.O.; Barili, F.; Bloch, K.D.; Bolger, A.F.; Botker, H.E.; Bozkurt, B.; Bugiardini, R.; Cannon, C.; de Lemos, J.; Eberli, F.R.; Escobar, E.; Hlatky, M.; James, S.; Kern, K.B.; Moliterno, D.J.; Mueller, C.; Neskovic, A.N.; Pieske, B.M.; Schulman, S.P.; Storey, R.F.; Taubert, K.A.; Vranckx, P.; Wagner, D.R. Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction; Authors/Task Force Members Chairpersons; Biomarker Subcommittee; ECG Subcommittee; Imaging Subcommittee; Classification Subcommittee; Intervention Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; ESC Committee for Practice Guidelines (CPG); Document Reviewers. Third universal definition of myocardial infarction. J. Am. Coll. Cardiol., 2012, 60(16), 1581-1598.
[http://dx.doi.org/10.1016/j.jacc.2012.08.001 ] [PMID: 22958960]
[42]
Libby, P. Mechanisms of acute coronary syndromes and their implications for therapy. N. Engl. J. Med., 2013, 368(21), 2004-2013.
[http://dx.doi.org/10.1056/NEJMra1216063 ] [PMID: 23697515]
[43]
Amsterdam, E.A.; Wenger, N.K.; Brindis, R.G.; Casey, D.E., Jr; Ganiats, T.G.; Holmes, D.R., Jr; Jaffe, A.S.; Jneid, H.; Kelly, R.F.; Kontos, M.C.; Levine, G.N.; Liebson, P.R.; Mukherjee, D.; Peterson, E.D.; Sabatine, M.S.; Smalling, R.W.; Zieman, S.J. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol., 2014, 64(24), e139-e228.
[http://dx.doi.org/10.1016/j.jacc.2014.09.017 ] [PMID: 25260718]
[44]
Rossi, G.P. Dual ACE and NEP inhibitors: A review of the pharmacological properties of MDL 100240. Cardiovasc. Drug Rev., 2003, 21(1), 51-66.
[http://dx.doi.org/10.1111/j.1527-3466.2003.tb00105.x ] [PMID: 12595917]
[45]
Bralet, J.; Marie, C.; Gros, C.; Schwartz, J.C.; Lecomte, J.M. Fasidotril: The first dual Inhibitor of Neprilysin and ACE. Cardiovasc. Drug Rev., 2006, 18, 1-24.
[http://dx.doi.org/10.1111/j.1527-3466.2000.tb00030.x]
[46]
Gregg, A.; Bottle, S.E.; Devine, S.M.; Figler, H.; Linden, J.; White, P.; Pouton, C.W.; Urmaliya, V.; Scammells, P.J. Dual acting antioxidant A1 adenosine receptor agonists. Bioorg. Med. Chem. Lett., 2007, 17(19), 5437-5441.
[http://dx.doi.org/10.1016/j.bmcl.2007.07.035 ] [PMID: 17689079]
[47]
Aurelio, L.; Valant, C.; Flynn, B.L.; Sexton, P.M.; Christopoulos, A.; Scammells, P.J. Allosteric modulators of the adenosine A1 receptor: Synthesis and pharmacological evaluation of 4-substituted 2-amino-3-benzoylthiophenes. J. Med. Chem., 2009, 52(14), 4543-4547.
[http://dx.doi.org/10.1021/jm9002582 ] [PMID: 19514747]
[48]
Vecchio, E.A.; Chuo, C.H.; Baltos, J-A.; Ford, L.; Scammells, P.J.; Wang, B.H.; Christopoulos, A.; White, P.J.; May, L.T. The hybrid molecule, VCP746, is a potent adenosine A2B receptor agonist that stimulates anti-fibrotic signalling. Biochem. Pharmacol., 2016, 117, 46-56.
[http://dx.doi.org/10.1016/j.bcp.2016.08.007 ] [PMID: 27520486]
[49]
Chang, L.; Wang, Z.; Ma, F.; Tran, B.; Zhong, R.; Xiong, Y.; Dai, T.; Wu, J.; Xin, X.; Guo, W.; Xie, Y.; Mao, Y.; Zhu, Y-Z. ZYZ-803 mitigates endoplasmic reticulum stress-related necroptosis after acute myocardial infarction through downregulating the RIP3-CaMKII signaling pathway. Oxid. Med. Cell. Longev., 2019, 2019, 6173685.
[http://dx.doi.org/10.1155/2019/6173685 ] [PMID: 31281585]
[50]
Cheng, Y.; Gong, Y.; Qian, S.; Mou, Y.; Li, H.; Chen, X.; Kong, H.; Xie, W.; Wang, H.; Zhang, Y.; Huang, Z. Identification of a novel hybridization from isosorbide 5-mononitrate and bardoxolone methyl with dual activities of pulmonary vasodilation and vascular remodeling inhibition on pulmonary arterial hypertension rats. J. Med. Chem., 2018, 61(4), 1474-1482.
[51]
Tran, T-A.; Kramer, B.; Shin, Y-J.; Vallar, P.; Boatman, P.D.; Zou, N.; Sage, C.R.; Gharbaoui, T.; Krishnan, A.; Pal, B.; Shakya, S.R.; Garrido Montalban, A.; Adams, J.W.; Ramirez, J.; Behan, D.P.; Shifrina, A.; Blackburn, A.; Leakakos, T.; Shi, Y.; Morgan, M.; Sadeque, A.; Chen, W.; Unett, D.J.; Gaidarov, I.; Chen, X.; Chang, S.; Shu, H-H.; Tung, S-F.; Semple, G. Discovery of 2- (((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): an orally active prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. J. Med. Chem., 2017, 60(3), 913-927.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00871 ] [PMID: 28072531]
[52]
Zheng, W.; Wang, Z.; Jiang, X.; Zhao, Q.; Shen, J. Targeted drugs for treatment of pulmonary arterial hypertension: Past, present, and future perspectives. J. Med. Chem., 2020, 63(24), 15153-15186.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01093 ] [PMID: 33314936]
[53]
Schermuly, R.T.; Ghofrani, H.A.; Wilkins, M.R.; Grimminger, F. Mechanisms of disease: Pulmonary arterial hypertension. Nat. Rev. Cardiol., 2011, 8(8), 443-455.
[http://dx.doi.org/10.1038/nrcardio.2011.87 ] [PMID: 21691314]
[54]
Veeroju, S.; Kojonazarov, B.; Weiss, A.; Ghofrani, H.A.; Weissmann, N.; Grimminger, F.; Seeger, W.; Novoyatleva, T.; Schermuly, R.T. Therapeutic potential of regorafenib-A multikinase inhibitor in pulmonary hypertension. Int. J. Mol. Sci., 2021, 22(3), 1502.
[http://dx.doi.org/10.3390/ijms22031502 ] [PMID: 33540939]
[55]
Wang, Z.; Jiang, X.; Zhang, X.; Tian, G.; Yang, R.; Wu, J.; Zou, X.; Liu, Z.; Yang, X.; Wu, C.; Shi, J.; Li, J.; Suo, J.; Wang, Y.; Zhang, R.; Xu, Z.; Gong, X.; He, Y.; Zhu, W.; Aisa, H.A.; Jiang, H.; Xu, Y.; Shen, J. Pharmacokinetics-driven optimization of 4(3 H)-pyrimidinones as phosphodiesterase type 5 inhibitors leading to TPN171, a clinical candidate for the treatment of pulmonary arterial hypertension. J. Med. Chem., 2019, 62(10), 4979-4990.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00123 ] [PMID: 31021628]
[56]
Bisserier, M.; Pradhan, N.; Hadri, L. Current and emerging therapeutic approaches to pulmonary hypertension. Rev. Cardiovasc. Med., 2020, 21(2), 163-179.
[http://dx.doi.org/10.31083/j.rcm.2020.02.597 ] [PMID: 32706206]
[57]
Galiè, N.; Ghofrani, H.A.; Torbicki, A.; Barst, R.J.; Rubin, L.J.; Badesch, D.; Fleming, T.; Parpia, T.; Burgess, G.; Branzi, A.; Grimminger, F.; Kurzyna, M.; Simonneau, G. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med., 2005, 353(20), 2148-2157.
[http://dx.doi.org/10.1056/NEJMoa050010 ] [PMID: 16291984]
[58]
Galiè, N.; Brundage, B.H.; Ghofrani, H.A.; Oudiz, R.J.; Simonneau, G.; Safdar, Z.; Shapiro, S.; White, R.J.; Chan, M.; Beardsworth, A.; Frumkin, L.; Barst, R.J. Tadalafil therapy for pulmonary arterial hypertension. Circulation, 2009, 119(22), 2894-2903.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.839274 ] [PMID: 19470885]
[59]
Olschewski, H.; Simonneau, G.; Galiè, N.; Higenbottam, T.; Naeije, R.; Rubin, L.J.; Nikkho, S.; Speich, R.; Hoeper, M.M.; Behr, J.; Winkler, J.; Sitbon, O.; Popov, W.; Ghofrani, H.A.; Manes, A.; Kiely, D.G.; Ewert, R.; Meyer, A.; Corris, P.A.; Delcroix, M.; Gomez-Sanchez, M.; Siedentop, H.; Seeger, W. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med., 2002, 347(5), 322-329.
[http://dx.doi.org/10.1056/NEJMoa020204 ] [PMID: 12151469]
[60]
Simonneau, G.; Barst, R.J.; Galie, N.; Naeije, R.; Rich, S.; Bourge, R.C.; Keogh, A.; Oudiz, R.; Frost, A.; Blackburn, S.D.; Crow, J.W.; Rubin, L.J. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med., 2002, 165(6), 800-804.
[http://dx.doi.org/10.1164/ajrccm.165.6.2106079 ] [PMID: 11897647]
[61]
Skoro-Sajer, N.; Lang, I.M. Selexipag for the treatment of pulmonary arterial hypertension. Expert Opin. Pharmacother., 2014, 15(3), 429-436.
[http://dx.doi.org/10.1517/14656566.2014.876007 ] [PMID: 24392948]
[62]
Channick, R.N.; Simonneau, G.; Sitbon, O.; Robbins, I.M.; Frost, A.; Tapson, V.F.; Badesch, D.B.; Roux, S.; Rainisio, M.; Bodin, F.; Rubin, L.J. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet, 2001, 358(9288), 1119-1123.
[http://dx.doi.org/10.1016/S0140-6736(01)06250-X ] [PMID: 11597664]
[63]
Pulido, T.; Adzerikho, I.; Channick, R.N.; Delcroix, M.; Galiè, N.; Ghofrani, H-A.; Jansa, P.; Jing, Z-C.; Le Brun, F-O.; Mehta, S.; Mittelholzer, C.M.; Perchenet, L.; Sastry, B.K.S.; Sitbon, O.; Souza, R.; Torbicki, A.; Zeng, X.; Rubin, L.J.; Simonneau, G. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N. Engl. J. Med., 2013, 369(9), 809-818.
[http://dx.doi.org/10.1056/NEJMoa1213917 ] [PMID: 23984728]
[64]
Galiè, N.; Olschewski, H.; Oudiz, R.J.; Torres, F.; Frost, A.; Ghofrani, H.A.; Badesch, D.B.; McGoon, M.D.; McLaughlin, V.V.; Roecker, E.B.; Gerber, M.J.; Dufton, C.; Wiens, B.L.; Rubin, L.J. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation, 2008, 117(23), 3010-3019.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.742510 ] [PMID: 18506008]
[65]
Hambly, N.; Granton, J. Riociguat for the treatment of pulmonary hypertension. Expert Rev. Respir. Med., 2015, 9(6), 679-695.
[http://dx.doi.org/10.1586/17476348.2015.1106316 ] [PMID: 26599488]
[66]
Bolli, M.H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist. J. Med. Chem., 2012, 55(17), 7849-7861.
[http://dx.doi.org/10.1021/jm3009103 ] [PMID: 22862294]
[67]
Böhm, F.; Pernow, J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc. Res., 2007, 76(1), 8-18.
[http://dx.doi.org/10.1016/j.cardiores.2007.06.004 ] [PMID: 17617392]
[68]
Rubin, L.J. Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci., 2012, 91(13-14), 517-521.
[http://dx.doi.org/10.1016/j.lfs.2012.07.033 ] [PMID: 22884806]
[69]
Cai, J.; Chen, J.; Cao, M.; Wang, P.; Feng, C.; Ji, M. Design, synthesis, and biological evaluation of benzofuran derivatives as ET receptor antagonists. Med. Chem. Res., 2013, 22, 5472-5480.
[http://dx.doi.org/10.1007/s00044-013-0542-3]
[70]
Kaltenbronn, J.; Quin, J.; Reisdorph, B.; Klutchko, S.; Reynolds, E.; Welch, K.; Flynn, M.; Doherty, A. Benzofuran derivatives as ETA-selective, non-peptide endothelin antagonists. Eur. J. Med. Chem., 1997, 32, 425-431.
[http://dx.doi.org/10.1016/S0223-5234(97)81679-0]
[71]
Lian, T-Y.; Jiang, X.; Jing, Z-C. Riociguat: A soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Drug Des. Devel. Ther., 2017, 11, 1195-1207.
[http://dx.doi.org/10.2147/DDDT.S117277 ] [PMID: 28458514]
[72]
Boutou, A.K.; Pitsiou, G. Treatment of pulmonary hypertension with riociguat: A review of current evidence and future perspectives. Expert Opin. Pharmacother., 2020, 21(10), 1145-1155.
[http://dx.doi.org/10.1080/14656566.2020.1727446 ] [PMID: 32089012]
[73]
Abman, S.H. Inhaled nitric oxide for the treatment of pulmonary arterial hypertension. In: Pharmacotherapy of Pulmonary Hypertension; Humbert, M.; Evgenov, O.V.; Stasch, J-P., Eds.; Handbook of Experimental Pharmacology. Springer: Berlin, Heidelberg, 2013; 218, pp. 257-276.
[http://dx.doi.org/10.1007/978-3-662-45805-1_11]
[74]
Mercurio, V.; Bianco, A.; Campi, G.; Cuomo, A.; Diab, N.; Mancini, A.; Parrella, P.; Petretta, M.; Hassoun, P.M.; Bonaduce, D. New drugs, therapeutic strategies, and future direction for the treatment of pulmonary arterial hypertension. Curr. Med. Chem., 2019, 26(16), 2844-2864.
[http://dx.doi.org/10.2174/0929867325666180201095743 ] [PMID: 29421995]
[75]
Hu, L.; Li, L.; Chang, Q.; Fu, S.; Qin, J.; Chen, Z.; Li, X.; Liu, Q.; Hu, G.; Li, Q. Discovery of novel pyrazolo[3,4-b] pyridine derivatives with dual activities of vascular remodeling inhibition and vasodilation for the treatment of pulmonary arterial hypertension. J. Med. Chem., 2020, 63(19), 11215-11234.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01132 ] [PMID: 32914624]
[76]
Li, M.X.; Jiang, D.Q.; Wang, Y.; Chen, Q.Z.; Ma, Y.J.; Yu, S.S.; Wang, Y. Signal mechanisms of vascular remodeling in the development of pulmonary arterial hypertension. J. Cardiovasc. Pharmacol., 2016, 67(2), 182-190.
[http://dx.doi.org/10.1097/FJC.0000000000000328 ] [PMID: 26448276]
[77]
Luo, F.; Wu, L.; Xie, G.; Gao, F.; Zhang, Z.; Chen, G.; Liu, Z.; Zha, L.; Zhang, G.; Sun, Y.; Zhang, Z.; Wang, Y. Dual-functional MN-08 attenuated pulmonary arterial hypertension through vasodilation and inhibition of pulmonary arterial remodeling. Hypertension, 2021, 77(5), 1787-1798.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15994 ] [PMID: 33775126]
[78]
Kümmerle, A.E.; Schmitt, M.; Cardozo, S.V.S.; Lugnier, C.; Villa, P.; Lopes, A.B.; Romeiro, N.C.; Justiniano, H.; Martins, M.A.; Fraga, C.A.M.; Bourguignon, J-J.; Barreiro, E.J. Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors. J. Med. Chem., 2012, 55(17), 7525-7545.
[http://dx.doi.org/10.1021/jm300514y ] [PMID: 22891752]
[79]
Bastos, I.T.S.; Pinheiro, P.S.M.; Costa, F.N.; Rocha, M.D.; Sant’Anna, C.M.R.; Braz, D.; Souza, E.T.; Martins, M.A.; Barreiro, E.J.; Ferreira, F.F.; Barroso, R.C.; Fraga, C.A.M. Design, synthesis, experimental and theoretical characterization of a new multitarget 2-thienyl-N-acylhydrazone derivative. Pharmaceuticals (Basel), 2018, 11(4), 119.
[http://dx.doi.org/10.3390/ph11040119 ] [PMID: 30388818]
[80]
Leal, C.M.; Pereira, S.L.; Kümmerle, A.E.; Leal, D.M.; Tesch, R.; de Sant’Anna, C.M.R.; Fraga, C.A.M.; Barreiro, E.J.; Sudo, R.T.; Zapata-Sudo, G. Antihypertensive profile of 2-thienyl-3,4-methylenedioxybenzoylhydrazone is mediated by activation of the A2A adenosine receptor. Eur. J. Med. Chem., 2012, 55, 49-57.
[http://dx.doi.org/10.1016/j.ejmech.2012.06.056 ] [PMID: 22857782]
[81]
Nadur, N.F.; de Azevedo, L.L.; Caruso, L.; Graebin, C.S.; Lacerda, R.B.; Kümmerle, A.E. The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure. Eur. J. Med. Chem., 2021, 212, 113123.
[http://dx.doi.org/10.1016/j.ejmech.2020.113123 ] [PMID: 33412421]
[82]
Li, H-H.; Hsu, H-H.; Chang, G-J.; Chen, I-C.; Ho, W-J.; Hsu, P-C.; Chen, W-J.; Pang, J.S.; Huang, C-C.; Lai, Y-J. Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol., 2018, 314(3), L349-L359.
[http://dx.doi.org/10.1152/ajplung.00245.2017 ] [PMID: 29146573]
[83]
Lai, Y-J.; Pullamsetti, S.S.; Dony, E.; Weissmann, N.; Butrous, G.; Banat, G-A.; Ghofrani, H.A.; Seeger, W.; Grimminger, F.; Schermuly, R.T. Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension. Am. J. Respir. Crit. Care Med., 2008, 178(2), 188-196.
[http://dx.doi.org/10.1164/rccm.200710-1519OC ] [PMID: 18467507]
[84]
Hansmann, G.; Wagner, R.A.; Schellong, S.; Perez, V.A.; Urashima, T.; Wang, L.; Sheikh, A.Y.; Suen, R.S.; Stewart, D.J.; Rabinovitch, M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation. Circulation, 2007, 115(10), 1275-1284.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.663120 ] [PMID: 17339547]
[85]
Xia, J.; Yang, L.; Dong, L.; Niu, M.; Zhang, S.; Yang, Z.; Wumaier, G.; Li, Y.; Wei, X.; Gong, Y.; Zhu, N.; Li, S. Cefminox, a dual agonist of prostacyclin receptor and peroxisome proliferator-activated receptor-gamma identified by virtual screening, has therapeutic efficacy against hypoxia-induced pulmonary hypertension in rats. Front. Pharmacol., 2018, 9, 134.
[http://dx.doi.org/10.3389/fphar.2018.00134 ] [PMID: 29527168]
[86]
Richeldi, L.; du Bois, R.M.; Raghu, G.; Azuma, A.; Brown, K.K.; Costabel, U.; Cottin, V.; Flaherty, K.R.; Hansell, D.M.; Inoue, Y.; Kim, D.S.; Kolb, M.; Nicholson, A.G.; Noble, P.W.; Selman, M.; Taniguchi, H.; Brun, M.; Le Maulf, F.; Girard, M.; Stowasser, S.; Schlenker-Herceg, R.; Disse, B.; Collard, H.R. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med., 2014, 370(22), 2071-2082.
[http://dx.doi.org/10.1056/NEJMoa1402584 ] [PMID: 24836310]
[87]
Tsutsumi, T.; Nagaoka, T.; Yoshida, T.; Wang, L.; Kuriyama, S.; Suzuki, Y.; Nagata, Y.; Harada, N.; Kodama, Y.; Takahashi, F.; Morio, Y.; Takahashi, K. Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation. PLoS One, 2019, 14(7), e0214697.
[http://dx.doi.org/10.1371/journal.pone.0214697 ] [PMID: 31339889]
[88]
Noskovičová, N.; Petřek, M.; Eickelberg, O.; Heinzelmann, K. Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies. Am. J. Respir. Cell Mol. Biol., 2015, 52(3), 263-284.
[http://dx.doi.org/10.1165/rcmb.2014-0294TR ] [PMID: 25303647]
[89]
Ranchoux, B.; Antigny, F.; Rucker-Martin, C.; Hautefort, A.; Péchoux, C.; Bogaard, H.J.; Dorfmüller, P.; Remy, S.; Lecerf, F.; Planté, S.; Chat, S.; Fadel, E.; Houssaini, A.; Anegon, I.; Adnot, S.; Simonneau, G.; Humbert, M.; Cohen-Kaminsky, S.; Perros, F. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation, 2015, 131(11), 1006-1018.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.008750 ] [PMID: 25593290]
[90]
Xiao, Y-F. Cardiac arrhythmia and heart failure: From bench to bedside. J. Geriatr. Cardiol., 2011, 8(3), 131-132.
[http://dx.doi.org/10.3724/SP.J.1263.2011.00131 ] [PMID: 22783298]
[91]
Albert, C.M.; Stevenson, W.G. The future of arrhythmias and electrophysiology. Circulation, 2016, 133(25), 2687-2696.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023519 ] [PMID: 27324363]
[92]
Jones, B.; Burnand, C. Antiarrhythmic drugs. Anaesth. Intensive Care Med., 2021, 22, 319-323.
[http://dx.doi.org/10.1016/j.mpaic.2021.03.009]
[93]
Adebesin, A.M.; Wesser, T.; Vijaykumar, J.; Konkel, A.; Paudyal, M.P.; Lossie, J.; Zhu, C.; Westphal, C.; Puli, N.; Fischer, R.; Schunck, W-H.; Falck, J.R. Development of robust 17(R),18(S)-epoxyeicosatetraenoic acid (17,18-EEQ) analogues as potential clinical antiarrhythmic agents. J. Med. Chem., 2019, 62(22), 10124-10143.
[PMID: 31693857]
[94]
Kattoor, A.J.; Pothineni, N.V.K.; Palagiri, D.; Mehta, J.L. Oxidative stress in atherosclerosis. Curr. Atheroscler. Rep., 2017, 19(11), 42.
[http://dx.doi.org/10.1007/s11883-017-0678-6 ] [PMID: 28921056]
[95]
Lefer, D.J.; Granger, D.N. Oxidative stress and cardiac disease. Am. J. Med., 2000, 109(4), 315-323.
[http://dx.doi.org/10.1016/S0002-9343(00)00467-8 ] [PMID: 10996583]
[96]
De Bellis, M.; De Luca, A.; Desaphy, J.F.; Carbonara, R.; Heiny, J.A.; Kennedy, A.; Carocci, A.; Cavalluzzi, M.M.; Lentini, G.; Franchini, C.; Camerino, D.C. Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels. Biophys. J., 2013, 104(2), 344-354.
[http://dx.doi.org/10.1016/j.bpj.2012.11.3830 ] [PMID: 23442856]
[97]
Carocci, A.; Catalano, A.; Bruno, C.; Lentini, G.; Franchini, C.; De Bellis, M.; De Luca, A.; Conte Camerino, D. Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs. Chirality, 2010, 22(3), 299-307.
[http://dx.doi.org/10.1002/chir.20741 ] [PMID: 19544349]
[98]
Demirpençe, E.; Caner, H.; Bavbek, M.; Kilinç, K. Antioxidant action of the antiarrhythmic drug mexiletine in brain membranes. Jpn. J. Pharmacol., 1999, 81(1), 7-11.
[http://dx.doi.org/10.1016/S0021-5198(19)30802-9 ] [PMID: 10580364]
[99]
Roselli, M.; Carocci, A.; Budriesi, R.; Micucci, M.; Toma, M.; Di Cesare Mannelli, L.; Lovece, A.; Catalano, A.; Cavalluzzi, M.M.; Bruno, C.; De Palma, A.; Contino, M.; Perrone, M.G.; Colabufo, N.A.; Chiarini, A.; Franchini, C.; Ghelardini, C.; Habtemariam, S.; Lentini, G. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues. Eur. J. Med. Chem., 2016, 121, 300-307.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.046 ] [PMID: 27267000]
[100]
Carocci, A.; Roselli, M.; Budriesi, R.; Micucci, M.; Desaphy, J-F.; Altamura, C.; Cavalluzzi, M.M.; Toma, M.; Passeri, G.I.; Milani, G.; Lovece, A.; Catalano, A.; Bruno, C.; De Palma, A.; Corbo, F.; Franchini, C.; Habtemariam, S.; Lentini, G. Synthesis and evaluation of voltage-gated sodium channel blocking pyrroline derivatives endowed with both antiarrhythmic and antioxidant activities. ChemMedChem, 2021, 16(3), 578-588.
[http://dx.doi.org/10.1002/cmdc.202000692 ] [PMID: 33015979]
[101]
Loussouarn, G.; Sternberg, D.; Nicole, S.; Marionneau, C.; Le Bouffant, F.; Toumaniantz, G.; Barc, J.; Malak, O.A.; Fressart, V.; Péréon, Y.; Baró, I.; Charpentier, F. Physiological and pathophysiological insights of Nav1.4 and Nav1.5 comparison. Front. Pharmacol., 2016, 6, 314.
[http://dx.doi.org/10.3389/fphar.2015.00314 ] [PMID: 26834636]
[102]
de Lera Ruiz, M.; Kraus, R.L. Voltage-gated sodium channels: Structure, function, pharmacology, and clinical indications. J. Med. Chem., 2015, 58(18), 7093-7118.
[http://dx.doi.org/10.1021/jm501981g ] [PMID: 25927480]
[103]
Catterall, W.A. Forty years of sodium channels: Structure, function, pharmacology, and epilepsy. Neurochem. Res., 2017, 42(9), 2495-2504.
[http://dx.doi.org/10.1007/s11064-017-2314-9 ] [PMID: 28589518]
[104]
Klint, J.K.; Senff, S.; Rupasinghe, D.B.; Er, S.Y.; Herzig, V.; Nicholson, G.M.; King, G.F. Spider-venom peptides that target voltage-gated sodium channels: Pharmacological tools and potential therapeutic leads. Toxicon Off. J. Int. Soc. Toxinology, 2012, 60(4), 478-491.
[http://dx.doi.org/10.1016/j.toxicon.2012.04.337 ] [PMID: 22543187]
[105]
Xu, Y.; Sun, J.; Liu, H.; Sun, J.; Yu, Y.; Su, Y.; Cui, Y.; Zhao, M.; Zhang, J. Scorpion toxins targeting voltage-gated sodium channels associated with pain. Curr. Pharm. Biotechnol., 2018, 19(11), 848-855.
[http://dx.doi.org/10.2174/1389201019666181105160744 ] [PMID: 30398114]
[106]
Jin, A-H.; Muttenthaler, M.; Dutertre, S.; Himaya, S.W.A.; Kaas, Q.; Craik, D.J.; Lewis, R.J.; Alewood, P.F. Conotoxins: Chemistry and biology. Chem. Rev., 2019, 119(21), 11510-11549.
[http://dx.doi.org/10.1021/acs.chemrev.9b00207 ] [PMID: 31633928]
[107]
Israel, M.R.; Tay, B.; Deuis, J.R.; Vetter, I. Sodium channels and venom peptide pharmacology. Adv. Pharmacol., 2017, 79, 67-116.
[http://dx.doi.org/10.1016/bs.apha.2017.01.004 ] [PMID: 28528674]
[108]
Peschel, A.; Cardoso, F.C.; Walker, A.A.; Durek, T.; Stone, M.R.L.; Braga Emidio, N.; Dawson, P.E.; Muttenthaler, M.; King, G.F. Two for the price of one: Heterobivalent ligand design targeting two binding sites on voltage-gated sodium channels slows ligand dissociation and enhances potency. J. Med. Chem., 2020, 63(21), 12773-12785.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01107 ] [PMID: 33078946]
[109]
Zhang, M-M.; Green, B.R.; Catlin, P.; Fiedler, B.; Azam, L.; Chadwick, A.; Terlau, H.; McArthur, J.R.; French, R.J.; Gulyas, J.; Rivier, J.E.; Smith, B.J.; Norton, R.S.; Olivera, B.M.; Yoshikami, D.; Bulaj, G. Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels. J. Biol. Chem., 2007, 282(42), 30699-30706.
[http://dx.doi.org/10.1074/jbc.M704616200 ] [PMID: 17724025]
[110]
Peng, K.; Shu, Q.; Liu, Z.; Liang, S. Function and solution structure of huwentoxin-IV, a potent neuronal tetrodotoxin (TTX)-sensitive sodium channel antagonist from Chinese bird spider Selenocosmia huwena. J. Biol. Chem., 2002, 277(49), 47564-47571.
[http://dx.doi.org/10.1074/jbc.M204063200 ] [PMID: 12228241]
[111]
Xu, H.; Li, T.; Rohou, A.; Arthur, C.P.; Tzakoniati, F.; Wong, E.; Estevez, A.; Kugel, C.; Franke, Y.; Chen, J.; Ciferri, C.; Hackos, D.H.; Koth, C.M.; Payandeh, J. Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin. Cell, 2019, 176(4), 702-715.e14.
[http://dx.doi.org/10.1016/j.cell.2018.12.018 ] [PMID: 30661758]
[112]
Fu, D.G. Cardiac arrhythmias: Diagnosis, symptoms, and treatments. Cell Biochem. Biophys., 2015, 73(2), 291-296.
[http://dx.doi.org/10.1007/s12013-015-0626-4 ] [PMID: 25737133]
[113]
Pürerfellner, H. Recent developments in cardiovascular drug therapy: Treatment of atrial arrhythmias with new class III drugs and beyond. Curr. Med. Chem. Cardiovasc. Hematol. Agents, 2004, 2(1), 79-91.
[http://dx.doi.org/10.2174/1568016043477396 ] [PMID: 15320809]
[114]
So, P.P-S.; Hu, X-D.; Backx, P.H.; Puglisi, J.L.; Dorian, P. Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles. Br. J. Pharmacol., 2006, 148(3), 255-263.
[http://dx.doi.org/10.1038/sj.bjp.0706721 ] [PMID: 16565733]
[115]
So, P.P-S.; Backx, P.H.; Hu, X-D.; Dorian, P.I. (Ks) block by HMR 1556 lowers ventricular defibrillation threshold and reverses the repolarization shortening by isoproterenol without rate-dependence in rabbits. J. Cardiovasc. Electrophysiol., 2007, 18(7), 750-756.
[http://dx.doi.org/10.1111/j.1540-8167.2007.00812.x ] [PMID: 17578345]
[116]
Du, L.; Li, M.; Yang, Q.; Tang, Y.; You, Q.; Xia, L. Molecular hybridization, synthesis, and biological evaluation of novel chroman I(Kr) and I(Ks) dual blockers. Bioorg. Med. Chem. Lett., 2009, 19(5), 1477-1480.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.022 ] [PMID: 19185489]
[117]
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A.M. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14(17), 1829-1852.
[http://dx.doi.org/10.2174/092986707781058805 ] [PMID: 17627520]
[118]
Shah, S.A.; Kluger, J.; White, C.M. Monotherapy versus combination therapy with class III antiarrhythmic agents to attenuate transmural dispersion of repolarization: A potential risk factor for torsade de pointes. Pharmacotherapy, 2007, 27(9), 1297-1305.
[http://dx.doi.org/10.1592/phco.27.9.1297 ] [PMID: 17723083]
[119]
Savelieva, I.; Camm, J. Anti-arrhythmic drug therapy for atrial fibrillation: Current anti-arrhythmic drugs, investigational agents, and innovative approaches. Europace, 2008, 10(6), 647-665.
[http://dx.doi.org/10.1093/europace/eun130 ] [PMID: 18515286]
[120]
Hu, H.; Zhou, S.; Sun, X.; Xue, Y.; Yan, L.; Sun, X.; Lei, M.; Li, J.; Zeng, X.; Hao, L. A potent antiarrhythmic drug N-methyl berbamine extends the action potential through inhibiting both calcium and potassium currents. J. Pharmacol. Sci., 2020, 142(4), 131-139.
[http://dx.doi.org/10.1016/j.jphs.2019.12.008 ] [PMID: 31992491]
[121]
Kubacka, M.; Szkaradek, N.; Mogilski, S.; Pańczyk, K.; Siwek, A.; Gryboś, A.; Filipek, B.; Żmudzki, P.; Marona, H.; Waszkielewicz, A.M. Design, synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone. Bioorg. Med. Chem., 2018, 26(13), 3773-3784.
[http://dx.doi.org/10.1016/j.bmc.2018.04.038 ] [PMID: 29706529]
[122]
Rossignol, P.; Hernandez, A.F.; Solomon, S.D.; Zannad, F. Heart failure drug treatment. Lancet, 2019, 393(10175), 1034-1044.
[http://dx.doi.org/10.1016/S0140-6736(18)31808-7 ] [PMID: 30860029]
[123]
Normand, C.; Kaye, D.M.; Povsic, T.J.; Dickstein, K. Beyond pharmacological treatment: An insight into therapies that target specific aspects of heart failure pathophysiology. Lancet, 2019, 393(10175), 1045-1055.
[http://dx.doi.org/10.1016/S0140-6736(18)32216-5 ] [PMID: 30860030]
[124]
Ma, T.; Su, Y.; Song, J.; Xu, D. Treatment of heart failure with mid-range ejection fraction: A summary of current evidence. Front. Cardiovasc. Med., 2021, 8, 653336.
[http://dx.doi.org/10.3389/fcvm.2021.653336 ] [PMID: 34055935]
[125]
Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.F.; Coats, A.J.S.; Falk, V.; González-Juanatey, J.R.; Harjola, V-P.; Jankowska, E.A.; Jessup, M.; Linde, C.; Nihoyannopoulos, P.; Parissis, J.T.; Pieske, B.; Riley, J.P.; Rosano, G.M.C.; Ruilope, L.M.; Ruschitzka, F.; Rutten, F.H.; van der Meer, P. ESC Scientific Document Group 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J., 2016, 37(27), 2129-2200.
[http://dx.doi.org/10.1093/eurheartj/ehw128 ] [PMID: 27206819]
[126]
Volpe, M.; Tocci, G.; Battistoni, A.; Rubattu, S.; Angiotensin, I.I. Angiotensin II receptor blocker Neprilysin Inhibitor (ARNI): New avenues in cardiovascular therapy. High Blood Press. Cardiovasc. Prev., 2015, 22(3), 241-246.
[http://dx.doi.org/10.1007/s40292-015-0112-5 ] [PMID: 26100410]
[127]
Oliphant, C.S.; Owens, R.E.; Bolorunduro, O.B.; Jha, S.K. Ivabradine: A review of labeled and off-label uses. Am. J. Cardiovasc. Drugs, 2016, 16(5), 337-347.
[http://dx.doi.org/10.1007/s40256-016-0178-z ] [PMID: 27405864]
[128]
Frey, N.; Olson, E.N. Cardiac hypertrophy: The good, the bad, and the ugly. Annu. Rev. Physiol., 2003, 65, 45-79.
[http://dx.doi.org/10.1146/annurev.physiol.65.092101.142243 ] [PMID: 12524460]
[129]
Erten, Y.; Tulmac, M.; Derici, U.; Pasaoglu, H.; Altok Reis, K.; Bali, M.; Arinsoy, T.; Cengel, A.; Sindel, S. An association between inflammatory state and left ventricular hypertrophy in hemodialysis patients. Ren. Fail., 2005, 27(5), 581-589.
[http://dx.doi.org/10.1080/08860220500200072 ] [PMID: 16152997]
[130]
Kuusisto, J.; Kärjä, V.; Sipola, P.; Kholová, I.; Peuhkurinen, K.; Jääskeläinen, P.; Naukkarinen, A.; Ylä-Herttuala, S.; Punnonen, K.; Laakso, M. Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy. Heart, 2012, 98(13), 1007-1013.
[http://dx.doi.org/10.1136/heartjnl-2011-300960 ] [PMID: 22447464]
[131]
Silva-Cardoso, J.; Andrade, A.; Brito, D.; Ferreira, J.; Fonseca, C.; Peres, M.; Franco, F.; Moura, B. SGLT-2 inhibitors: A step forward in the treatment of heart failure with reduced ejection fraction. Rev. Port. Cardiol., 2021, 40(9), 687-693.
[http://dx.doi.org/10.1016/j.repce.2021.02.006 ] [PMID: 34503709]
[132]
Vaduganathan, M.; Butler, J.; Pitt, B.; Gheorghiade, M. Contemporary drug development in heart failure: Call for hemodynamically neutral therapies. Circ Heart Fail, 2015, 8(4), 826-831.
[http://dx.doi.org/10.1161/CIRCHEARTFAILURE.115.002271 ] [PMID: 26199309]
[133]
Pfeffer, M.A.; Braunwald, E.; Moyé, L.A.; Basta, L.; Brown, E.J., Jr; Cuddy, T.E.; Davis, B.R.; Geltman, E.M.; Goldman, S.; Flaker, G.C.; Klein, M.; Lamas, G.A.; Packer, M.; Rouleau, J.; Rouleau, J.L.; Rutherford, J.; Wertheimer, J.H.; Hawkins, C.M. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N. Engl. J. Med., 1992, 327(10), 669-677.
[http://dx.doi.org/10.1056/NEJM199209033271001 ] [PMID: 1386652]
[134]
Barnes, K.; Brown, C.; Turner, A.J. Endothelin-converting enzyme: ultrastructural localization and its recycling from the cell surface. Hypertension, 1998, 31(1), 3-9.
[http://dx.doi.org/10.1161/01.HYP.31.1.3 ] [PMID: 9449382]
[135]
González, W.; Soleilhac, J-M.; Fournié-Zaluski, M-C.; Roques, B.P.; Michel, J-B. Characterization of neutral endopeptidase in vascular cells, modulation of vasoactive peptide levels. Eur. J. Pharmacol., 1998, 345(3), 323-331.
[http://dx.doi.org/10.1016/S0014-2999(98)00038-7 ] [PMID: 9592033]
[136]
Vleeming, W.; van Amsterdam, J.G.C.; Stricker, B.H.C.; de Wildt, D.J. ACE inhibitor-induced angioedema. Incidence, prevention and management. Drug Saf., 1998, 18(3), 171-188.
[http://dx.doi.org/10.2165/00002018-199818030-00003 ] [PMID: 9530537]
[137]
Jandeleit-Dahm, K.A.M. Dual ACE/NEP inhibitors - more than playing the ACE card. J. Hum. Hypertens., 2006, 20(7), 478-481.
[http://dx.doi.org/10.1038/sj.jhh.1002018 ] [PMID: 16543904]
[138]
Hanessian, S.; Guesné, S.; Riber, L.; Marin, J.; Benoist, A.; Mennecier, P.; Rupin, A.; Verbeuren, T.J.; De Nanteuil, G. Targeting ACE and ECE with dual acting inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(3), 1058-1062.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.013 ] [PMID: 18160283]
[139]
Olimpieri, F.; Tambaro, S.; Fustero, S.; Lazzari, P.; Sanchez-Roselló, M.; Pani, L.; Volonterio, A.; Zanda, M. Synthesis and enzymatic evaluation of novel partially fluorinated thiol dual ACE/NEP inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(16), 4715-4719.
[http://dx.doi.org/10.1016/j.bmcl.2009.06.064 ] [PMID: 19596577]
[140]
Tambaro, S.; Reali, R.; Volonterio, A.; Zanda, M.; Olimpieri, F.; Pinna, G.A.; Lazzari, P. NESS002ie: A new fluorinated thiol endopeptidase inhibitor with antinociceptive activity in an animal model of persistent pain. Pharmacol. Biochem. Behav., 2013, 110, 137-144.
[http://dx.doi.org/10.1016/j.pbb.2013.06.008 ] [PMID: 23827651]
[141]
Jullien, N.; Makritis, A.; Georgiadis, D.; Beau, F.; Yiotakis, A.; Dive, V. Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors. J. Med. Chem., 2010, 53(1), 208-220.
[http://dx.doi.org/10.1021/jm9010803 ] [PMID: 19899765]
[142]
Kostis, J.B.; Packer, M.; Black, H.R.; Schmieder, R.; Henry, D.; Levy, E. Omapatrilat and enalapril in patients with hypertension: The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am. J. Hypertens., 2004, 17(2), 103-111.
[http://dx.doi.org/10.1016/j.amjhyper.2003.09.014 ] [PMID: 14751650]
[143]
McKinnell, R.M.; Fatheree, P.; Choi, S-K.; Gendron, R.; Jendza, K.; Olson Blair, B.; Budman, J.; Hill, C.M.; Hegde, L.G.; Yu, C.; McConn, D.; Hegde, S.S.; Marquess, D.G.; Klein, U. Discovery of TD-0212, an orally active dual pharmacology AT1 antagonist and Neprilysin Inhibitor (ARNI). ACS Med. Chem. Lett., 2018, 10(1), 86-91.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00462 ] [PMID: 30655952]
[144]
Yadav, M.R.; Naik, P.P.; Gandhi, H.P.; Chauhan, B.S.; Giridhar, R. Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism. Bioorg. Med. Chem. Lett., 2013, 23(13), 3959-3966.
[http://dx.doi.org/10.1016/j.bmcl.2013.04.054 ] [PMID: 23683590]
[145]
Agrawal, N.; Machhi, J.; Rathwa, V.; Kanhed, A.M.; Patel, S.; Murumkar, P.; Gandhi, H.; Yadav, M.R. Exploration of 6,7-dimethoxyquinazoline derivatives as dual acting α 1 - and AT 1 -receptor antagonists: Synthesis, evaluation, pharmacophore & 3D-QSAR modeling and receptor docking studies. RSC Advances, 2016, 6, 30661-30682.
[http://dx.doi.org/10.1039/C6RA00589F]
[146]
Ferrannini, G.; Savarese, G.; Rydén, L. Sodium-glucose transporter inhibition in heart failure: From an unexpected side effect to a novel treatment possibility. Diabetes Res. Clin. Pract., 2021, 175, 108796.
[http://dx.doi.org/10.1016/j.diabres.2021.108796 ] [PMID: 33845051]
[147]
Nightingale, B. A review of the proposed mechanistic actions of sodium glucose cotransporter-2 inhibitors in the treatment of heart failure. Cardiol. Res., 2021, 12(2), 60-66.
[http://dx.doi.org/10.14740/cr1221 ] [PMID: 33738008]
[148]
Anker, S.D.; Butler, J.; Filippatos, G.; Shahzeb Khan, M.; Ferreira, J.P.; Bocchi, E.; Böhm, M.; Brunner-La Rocca, H.P.; Choi, D-J.; Chopra, V.; Chuquiure, E.; Giannetti, N.; Gomez-Mesa, J.E.; Janssens, S.; Januzzi, J.L.; Gonzalez-Juanatey, J.R.; Merkely, B.; Nicholls, S.J.; Perrone, S.V.; Piña, I.L.; Ponikowski, P.; Senni, M.; Seronde, M-F.; Sim, D.; Spinar, J.; Squire, I.; Taddei, S.; Tsutsui, H.; Verma, S.; Vinereanu, D.; Zhang, J.; Jamal, W.; Schnaidt, S.; Schnee, J.M.; Brueckmann, M.; Pocock, S.J.; Zannad, F.; Packer, M. Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial. Eur. J. Heart Fail., 2020, 22(12), 2383-2392.
[http://dx.doi.org/10.1002/ejhf.2064 ] [PMID: 33251670]
[149]
Xu, G.; Du, F.; Kuo, G-H.; Xu, J.Z.; Liang, Y.; Demarest, K.; Gaul, M.D. 5,5-Difluoro- and 5-Fluoro-5-methyl-hexose-based C-Glucosides as potent and orally bioavailable SGLT1 and SGLT2 dual inhibitors. Bioorg. Med. Chem. Lett., 2020, 30(17), 127387.
[http://dx.doi.org/10.1016/j.bmcl.2020.127387 ] [PMID: 32738984]
[150]
Morphy, J.R.; Harris, C.J., Eds.; Designing Multi-Target Drugs, 21st ed; Royal Society of Chemistry: Cambridge, 2012.
[151]
Sandhu, D.; Antolin, A.A.; Cox, A.R.; Jones, A.M. Identification of different side effects between parp inhibitors and their polypharmacological multi-target rationale. Br. J. Clin. Pharmacol., 2022, 88(2), 742-752.
[http://dx.doi.org/10.1111/bcp.15015]

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