•• Kintscher U, Bakris GL, Kolkhof P. Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Br J Pharmacol. 2022;179:3220–34. This article provides in-depth overview over the pharmacodynamics and pharmacokinetics of all non-steroidal MRA, and discusses recent clinical data.

Article  CAS  PubMed  Google Scholar 

Mckenna NJ, O’Malley BW. From ligand to response: generating diversity in nuclear receptor coregulator function. J Steroid Biochem Mol Biol. 2000;74:351–6.

Article  CAS  PubMed  Google Scholar 

Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987;237:268–75.

Article  CAS  PubMed  Google Scholar 

Mckenna NJ, O’malley BW. SnapShot: nuclear receptors I. Cell. 2010;142(822–822): e821.

Google Scholar 

Grossmann C, Almeida-Prieto B, Nolze A, et al. Structural and molecular determinants of mineralocorticoid receptor signalling. Br J Pharmacol. 2022;179:3103–18.

Article  CAS  PubMed  Google Scholar 

Fuller PJ, Yang J, Young MJ. 30 Years of the mineralocorticoid receptor: coregulators as mediators of mineralocorticoid receptor signalling diversity. J Endocrinol. 2017;234:T23–34.

Article  CAS  PubMed  Google Scholar 

Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227–35.

Article  CAS  PubMed  Google Scholar 

Fraccarollo D, Berger S, Galuppo P, et al. Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation. 2011;123:400–8.

Article  CAS  PubMed  Google Scholar 

Lother A, Berger S, Gilsbach R, et al. Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. Hypertension. 2011;57:746–54.

Article  CAS  PubMed  Google Scholar 

Mccurley A, Pires PW, Bender SB, et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012;18:1429–33.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rickard AJ, Morgan J, Chrissobolis S, et al. Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure. Hypertension. 2014;63:1033–40.

Article  CAS  PubMed  Google Scholar 

Bertocchio JP, Warnock DG, Jaisser F. Mineralocorticoid receptor activation and blockade: an emerging paradigm in chronic kidney disease. Kidney international. 2011;79:1051–60.

Article  CAS  PubMed  Google Scholar 

Barbaro NR, Kirabo A, Harrison DG. A new role of mister (MR) T in hypertension: mineralocorticoid receptor, immune system, and hypertension. Circ Res. 2017;120:1527–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ferreira NS, Tostes RC, Paradis P, et al. Aldosterone, inflammation, immune system, and hypertension. American journal of hypertension. 2021;34:15–27.

Article  CAS  PubMed  Google Scholar 

Kolkhof P, Jaisser F, Kim SY, et al. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: comparison at bench and bedside. Handb Exp Pharmacol. 2017;243:271–305.

Article  CAS  PubMed  Google Scholar 

Fagart J, Hillisch A, Huyet J, et al. A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule. J Biol Chem. 2010;285:29932–40.

Article  PubMed  PubMed Central  Google Scholar 

Mcdonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726.

Article  CAS  PubMed  Google Scholar 

Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

Article  CAS  PubMed  Google Scholar 

Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.

Article  CAS  PubMed  Google Scholar 

Zannad F, Mcmurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

Article  CAS  PubMed  Google Scholar 

Agarwal R, Kolkhof P, Bakris G, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021;42:152–61.

Article  CAS  PubMed  Google Scholar 

Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351:543–51.

Article  CAS  PubMed  Google Scholar 

Nakamura T, Kawaguchi A. Phase 1 studies to define the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of the nonsteroidal mineralocorticoid receptor antagonist apararenone in healthy volunteers. Clin Pharmacol Drug Dev. 2021;10:353–65.

Article  CAS  PubMed  Google Scholar 

Nakamura T, Shimizu H, Kawaguchi A. Drug-drug interactions of the nonsteroidal mineralocorticoid receptor antagonist apararenone with midazolam, warfarin, and digoxin: a Phase 1 studies in healthy volunteers. Clin Ther. 2020;42(2171–2183): e2174.

Google Scholar 

Wada T, Inagaki M, Yoshinari T, et al. Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose-response study and open-label extension study. Clin Exp Nephrol. 2021;25:120–30.

Article  CAS  PubMed  Google Scholar 

Bamberg K, Johansson U, Edman K, et al. Preclinical pharmacology of AZD9977: a novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion. PLoS One. 2018;13: e0193380.

Article  PubMed  PubMed Central  Google Scholar 

Erlandsson F, Albayaty M, Chialda L, et al. Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator. Br J Clin Pharmacol. 2018;84:1486–93.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Whittaker A, Kragh AM, Hartleib-Geschwindner J, et al. Safety, tolerability, and pharmacokinetics of the mineralocorticoid receptor modulator AZD9977 in healthy men: a phase i multiple ascending dose study. Clin Transl Sci. 2020;13:275–83.

Article  CAS  PubMed  Google Scholar 

Arai K, Homma T, Morikawa Y, et al. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharmacol. 2015;761:226–34.

Article  CAS  PubMed  Google Scholar 

Arai K, Morikawa Y, Ubukata N, et al. CS-3150, a novel nonsteroidal mineralocorticoid receptor antagonist, shows preventive and therapeutic effects on renal injury in deoxycorticosterone acetate/salt-induced hypertensive rats. J Pharmacol Exp Ther. 2016;358:548–57.

Article  CAS  PubMed  Google Scholar 

Arai K, Tsuruoka H, Homma T. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J Pharmacol. 2015;769:266–73.

Article  CAS  PubMed  Google Scholar 

Ito S, Itoh H, Rakugi H, et al. Efficacy and safety of esaxerenone (CS-3150) for the treatment of essential hypertension: a phase 2 randomized, placebo-controlled, double-blind study. J Hum Hypertens. 2019;33:542–51.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ito S, Itoh H, Rakugi H, et al. Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction. Hypertens Res. 2021;44:489–97.

Article  CAS  PubMed  Google Scholar 

Ito S, Itoh H, Rakugi H, et al. Double-blind randomized Phase 3 study comparing esaxerenone (CS-3150) and Eplerenone in patients with essential hypertension (ESAX-HTN study). Hypertension. 2020;75:51–8.

Article  CAS  PubMed  Google Scholar 

Chow CP, Liu JR, Tan XJ, et al. Pharmacological profile of KBP-5074, a novel non-steroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal disease. J Drug Res Dev. 2017;3(2). https://doi.org/10.16966/2470-1009.137.

Bakris G, Yang YF, Pitt B. Mineralocorticoid receptor antagonists for hypertension management in advanced chronic kidney disease: BLOCK-CKD trial. Hypertension. 2020;76:144–9.

Article  CAS  PubMed  Google Scholar 

Barfacker 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;7:1385–403.

Article  PubMed  Google Scholar 

Pi