Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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

Future Anti-aldosterone Agents

Author(s): Kyriakos Dimitriadis*, Constantinos Tsioufis, Panayotis Iliakis, Alexandros Kasiakogias, Ioannis Andrikou, Ioannis Leontsinis, Dimitrios Konstantinidis and Dimitrios Tousoulis

Volume 24, Issue 46, 2018

Page: [5548 - 5554] Pages: 7

DOI: 10.2174/1381612825666190222145116

Price: $65

Abstract

Background: Targeting the renin-angiotensin-aldosterone axis is one of the most important therapeutic pathways for blood pressure control, renal and cardiovascular protection.

Objective: In this review, the new nonsteroidal mineralcorticoid receptor antagonists will be presented with a special focus on finerenone and its randomized controlled trials along with an introduction to the clinically promising aldosterone synthase inhibitors.

Method: We conducted an in-detail review of the literature in order to draft a narrative review on the field.

Results: Development of new anti-aldosterone agents focusing on the diverse components of aldosterone production and action is now taking place. Nonsteroidal mineralοcorticoid receptor antagonists are safe and effective therapeutic solutions with finerenone being the most well-studied agent with promising clinical data extending its efficacy in diabetes mellitus, chronic kidney disease and heart failure. Aldosterone synthase inhibitors impact the hormonal balance but there are still limitations regarding the duration of action and adverse effect of the glycolcorticoid axis.

Conclusion: Novel third-generation, nonsteroidal mineralocorticoid receptor antagonists seem to offer great advantages, which may lead to a wider use of mineralocorticoid receptor antagonists. Future randomized controlled trials are needed to evaluate significant perspectives.

Keywords: Mineralcorticoid receptor antagonists, finerenone, aldosterone synthase inhibitors, hyperkalemia, heart failure, diabetic nephropathy.

« Previous Next »
[1]
Sevá Pessôa B, van der Lubbe N, Verdonk K, Roks AJ, Hoorn EJ, Danser AH. Key developments in renin-angiotensin-aldosterone system inhibition. Nat Rev Nephrol 2013; 9(1): 26-36.
[2]
Ponikowski P, Voors AA, Anker SD, et al. 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): 2129-200.
[3]
Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018; 39(33): 3021-104.
[4]
Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 2004; 217(1-2): 67-74.
[5]
Tomaschitz A, Pilz S, Ritz E, Obermayer-Pietsch B, Pieber TR. Aldosterone and arterial hypertension. Nat Rev Endocrinol 2010; 6(2): 83-93.
[6]
Ruilope LM. Aldosterone, hypertension, and cardiovascular disease: An endless story. Hypertension 2008; 52(2): 207-8.
[7]
Doumas M, Boutari C, Tsioufis C, Dimitriadis K, Triantafyllou A, Douma S. Clinical Value of Measuring the Renin/Aldosterone Levels: Optimising the Management of Uncontrolled/Resistant Hypertension. Curr Vasc Pharmacol 2017; 16(1): 10-4.
[8]
Tsioufis C, Kordalis A, Flessas D, et al. Pathophysiology of resistant hypertension: the role of sympathetic nervous system. Int J Hypertens 2011; 2011: 642416.
[9]
Tsioufis C, Tsiachris D, Kasiakogias A, et al. Preclinical cardiorenal interrelationships in essential hypertension. Cardiorenal Med 2013; 3(1): 38-47.
[10]
Conn JW, Louis LH. Primary aldosteronism, a new clinical entity. Ann Intern Med 1956; 44(1): 1-15.
[11]
Conn JW, Fajans SS, Louis LH, Streeten DH, Johnson RD. Intermittent aldosteronism in periodic paralysis; dependence of attacks on retention of sodium, and failure to induce attacks by restriction of dietary sodium. Lancet 1957; 272(6973): 802-5.
[12]
Hargovan M, Ferro A. Aldosterone synthase inhibitors in hypertension: current status and future possibilities. JRSM Cardiovasc Dis 2014.
[13]
Tamargo M, Tamargo J. Future drug discovery in renin-angiotensin-aldosterone system intervention. Expert Opin Drug Discov 2017; 12(8): 827-48.
[14]
Brem AS, Gong R. Therapeutic targeting of aldosterone: A novel approach to the treatment of glomerular disease. Clin Sci (Lond) 2015; 128(9): 527-35.
[15]
Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res 2015; 116(6): 1074-95.
[16]
Deinum J, Riksen NP, Lenders JW. Pharmacological treatment of aldosterone excess. Pharmacol Ther 2015; 154: 120-33.
[17]
Pitt B, Zannad F, Remme WJ, et al. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996; 78(8): 902-7.
[18]
Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 2008; 118(16): 1643-50.
[19]
Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens 2002; 15(8): 709-16.
[20]
Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens 2015; 24(5): 417-24.
[21]
Bärfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: A nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem 2012; 7(8): 1385-403.
[22]
Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: A randomized, double-blind trial. Eur Heart J 2013; 34(31): 2453-63.
[23]
Kolkhof P, Borden SA. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol Cell Endocrinol 2012; 350(2): 310-7.
[24]
Bakris GL, Agarwal R, Chan JC, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA 2015; 314(9): 884-94.
[25]
Katayama S, Yamada D, Nakayama M, et al. A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy. J Diabetes Complications 2017; 31(4): 758-65.
[26]
Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016; 37(27): 2105-14.
[27]
Pitt B, Anker SD, Böhm M, et al. Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): A randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease. Eur J Heart Fail 2015; 17(2): 224-32.
[28]
Sato N, Ajioka M, Yamada T, et al. A Randomized Controlled Study of Finerenone vs Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease. Circulation: official journal of the Japanese Circ J. 2016. 80: 1113-22.
[29]
Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant 2013; 28(1): 36-43.
[30]
Mulder P, Mellin V, Favre J, et al. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: A comparison with spironolactone. Eur Heart J 2008; 29(17): 2171-9.
[31]
Abdel-Magid AF. Aldosterone synthase inhibitors: targeting chronic kidney disease and diabetic nephropathy. ACS Med Chem Lett 2013; 4(2): 157-8.
[32]
Yin L, Hu Q, Emmerich J, et al. Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors. J Med Chem 2014; 57(12): 5179-89.
[33]
Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin PF. Aldosterone synthase inhibition with LCI699: A proof-of-concept study in patients with primary aldosteronism. Hypertension 2010; 56(5): 831-8.
[34]
Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 2011; 124(18): 1945-55.
[35]
Schumacher CD, Steele RE, Brunner HR. Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy. J Hypertens 2013; 31(10): 2085-93.
[36]
Karns AD, Bral JM, Hartman D, Peppard T, Schumacher C. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens (Greenwich) 2013; 15(3): 186-92.
[37]
Amar L, Azizi M, Menard J, Peyrard S, Plouin PF. Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism. J Hypertens 2013; 31(3): 624-9.
[38]
Faselis C, Boutari C, Doumas M, Imprialos K, Stavropoulos K, Kokkinos P. Novel drugs for hypertension and heart failure: struggling for a place under the sum. Curr Pharm Des 2017; 23(10): 1540-50.

Rights & Permissions Print Cite
Article Metrics
91
15
1
1
World Health Day
© 2024 Bentham Science Publishers | Privacy Policy