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Nonsteroidal antagonists of the mineralocorticoid receptor

Kolkhof, Petera; Nowack, Christinab; Eitner, Franka

Current Opinion in Nephrology and Hypertension: September 2015 - Volume 24 - Issue 5 - p 417–424
doi: 10.1097/MNH.0000000000000147
PHARMACOLOGY AND THERAPEUTICS: Edited by Adam Whaley-Connell and C. John Sperati

Purpose of review The broad clinical use of steroidal mineralocorticoid receptor antagonists (MRAs) is limited by the potential risk of inducing hyperkalemia when given on top of renin–angiotensin system blockade. Drug discovery campaigns have been launched aiming for the identification of nonsteroidal MRAs with an improved safety profile. This review analyses the evidence for the potential of improved safety profiles of nonsteroidal MRAs and the current landscape of clinical trials with nonsteroidal MRAs.

Recent findings At least three novel nonsteroidal MRAs have reportedly demonstrated an improved therapeutic index (i.e. less risk for hyperkalemia) in comparison to steroidal antagonists in preclinical models. Five pharmaceutical companies have nonsteroidal MRAs in clinical development with a clear focus on the treatment of chronic kidney diseases. No clinical data have been published so far for MT-3995 (Mitsubishi), SC-3150 (Daiichi-Sankyo), LY2623091 (Eli Lilly) and PF-03882845 (Pfizer). In contrast, data from two clinical phase II trials are available for finerenone (Bayer) which demonstrated safety and efficacy in patients with heart failure and additional chronic kidney diseases, and significantly reduced albuminuria in patients with diabetic nephropathy. Neither hyperkalemia nor reductions in kidney function were limiting factors to its use.

Summary Novel, nonsteroidal MRAs are currently tested in clinical trials. Based on preclinical and first clinical data, these nonsteroidal MRAs might overcome the limitations of today's steroidal antagonists.

aGlobal Drug Discovery, Cardiology Research

bGlobal Clinical Development, Bayer Healthcare Pharmaceuticals, Wuppertal, Germany

Correspondence to Dr Peter Kolkhof, Cardiology Research, Bayer Healthcare Pharmaceuticals, Building 500, Aprather Weg 18a, 42096 Wuppertal, Germany. Tel: +49 202365475; fax: +49 202368009; e-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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Pathological overactivation of the mineralocorticoid receptor plays a critical and causative role in the pathogenesis of a variety of different cardiovascular diseases [1▪▪,2,3]. Accordingly, blockade of mineralocorticoid receptor has proven clinical efficacy in patients with heart failure with reduced ejection fraction, arterial hypertension and chronic kidney diseases (CKD) [1▪▪,4▪,5▪]. Current attempts to block aldosterone's action at the mineralocorticoid receptor by using the available steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone or eplerenone might, however, cause a dilemma for the responsible physician; although these drugs could be a life-saving therapy for patients with heart failure [6], they may also induce severe hyperkalemia and kidney dysfunction, particularly when given on top of standard of care angiotensin converting enzyme inhibitors or angiotensin receptor blockers to ‘real life’ patients, typically with variable degrees of concomitant kidney dysfunction. In fact, hyperkalemic episodes were reported in up to 36% among unselected elderly heart failure outpatients with about 10% developing potential life-threatening serum potassium levels of greater than 6 mmol/l [7,8].

Consequently, drug discovery programs within several pharmaceutical companies are aiming to identify novel nonsteroidal MRAs with potentially different pharmacodynamic properties. Recent reviews have already addressed some aspects of these efforts [9–12,13▪]. This review will serve two key purposes: first, it provides a current overview of preclinical and clinical studies using nonsteroidal MRAs with a particular focus on recent clinical trials, and second, it summarizes our current knowledge of differences in the mode of action between steroidal MRAs and the novel, nonsteroidal MRA finerenone.

Box 1

Box 1

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Table 1 summarizes the current landscape of nonsteroidal MRAs in clinical development [14–18]. At least five pharmaceutical companies have novel, nonsteroidal MRAs in clinical study development (source: with a clear focus on the treatment of patients with CKD. Additional compounds are in preclinical development [13▪]. The chemical structures have only been revealed for two compounds under clinical development (Table 2) [19,20]: Bayer's finerenone [21] and Pfizer's PF-03882845 [22]; however, more structural information is available for pharmaceutical compounds in preclinical studies.

Table 1

Table 1

Table 2

Table 2

Researchers at Merck identified oxazolidinedione derivatives as novel, nonsteroidal MRAs [23,24]. Representative compounds demonstrated acceptable in-vitro potency and selectivity but no pharmacodynamic in-vivo data have been published.

Dainippon Sumitomo discovered the nonsteroidal MRA SM-368229, possessing moderate selectivity towards other steroid receptors [25,26]. In spontaneously hypertensive rats, SM-368229 decreased systolic blood pressure at doses between 1 and 10 mg/kg without serum potassium elevation, whereas treatment with spironolactone decreased blood pressure at doses of 100 and 300 mg/kg with concomitant elevation of serum potassium at 300 mg/kg [27]. These results may suggest an improved therapeutic index of SM-368229 in comparison to spironolactone. To date, no clinical study has, however, been announced for SM-368229. Very recently, Nariai et al.[28▪] presented preclinical data of another Dainippon Sumitomo MRA called DSR-71167, which also weakly blocks carbonic anhydrase. DSR-71167, in contrast to spironolactone and eplerenone, did not cause elevation of serum potassium levels in potassium-loaded rats. Carbonic anhydrase inhibition may increase urinary potassium and therefore may avoid the development of hyperkalemia, at least from a theoretical point of view.

Researchers at Takeda identified benzoxazin-3-one derivatives, as novel, nonsteroidal MRAs [29–31]. Initially, selected lead compounds still had moderate affinity at the progesterone receptor, whereas related dihydropyrrol-2-one derivatives exhibited moderate and partial mineralocorticoid receptor agonistic activity at higher concentrations (30% activation at 10 μM). A novel, benzoxazin-3-one derivative has recently been presented which significantly lowered the blood pressure of deoxycorticosterone acetate/salt hypertensive rats after oral application [31].

LY2623091 (Eli Lilly, Table 1) entered clinical phase I trials in October 2010 and has been investigated in a small phase IIa trial in 48 patients with CKD until March 2013. Recently, Lilly announced the start of a larger phase II trial, this time, however, among 300 hypertensive patients, which may indicate a refocussing of this nonsteroidal MRA on the therapy of arterial hypertension. Lilly has also investigated LY3045697 in two small phase I studies in healthy volunteers during 2013 in The Netherlands. No published data on these novel MRAs are available.

Mitsubishi is currently conducting its nonsteroidal MRA MT-3995 in small phase IIa studies in Japan and two studies in Eastern Europe (n = 30–90) among patients with diabetic nephropathy [32] (Table 1).

CS-3150 is a novel, nonsteroidal MRA which was discovered by Exelixis and out-licensed to Daiichi-Sankyo in 2006. In January 2015, Daiichi-Sankyo announced the start of two different phase II studies: a dose-finding study in Japanese patients with T2DM and microalbuminuria [33] and a study to evaluate efficacy and safety of CS-3150 in Japanese patients with hypertension (estimated enrollment: 400 patients) [34] (Table 1).

Pfizer investigated the nonsteroidal MRA PF-03882845 (Tables 1 and 2) in preclinical as well in several clinical phase I studies. This compound was characterized as potent and selective MRA in vitro, which demonstrated a striking reduction of blood pressure and improved renal protection in comparison to eplerenone in a preclinical model of salt-induced hypertension and nephropathy [22]. Orena et al.[35] determined the respective plasma drug concentrations of eplerenone and PF-03882845 that were necessary to decrease urinary albumin and to increase serum potassium in a rat kidney injury model and calculated a therapeutic index, i.e., the ratio of the half maximal effective concentration (EC50) for increasing serum potassium to the respective EC50 for urinary albumin lowering. This ratio was 1.47 for eplerenone and 83.8 for PF-03882845. The compound was advanced to clinical phase I in 2009, to a multiple dose application trial in healthy volunteers that was, however, terminated based on safety concerns ( NCT00856258). Several further phase I trials with PF-03882845 have been conducted up to 2012 (Table 1). The last study (NCT01488877) was, however, terminated in July 2012, reportedly ‘for strategic reasons’. Recently, Pfizer published the chemical structures of possible back-up compounds of PF-03882845 [36] including a new class of aryl sulfonamide-based nonsteroidal MRAs [37].

The compound that is currently most advanced in clinical development is Bayer's finerenone which has, up to today, been investigated in more than 2000 patients in a phase IIa (ARTS [14,15]) and two phase IIb trials (ARTS-DN [16,17▪▪] and ARTS-HF [18]) (Tables 1 and 2). Finerenone has been investigated in different preclinical animal models of chronic hypertensive and ischemic heart and kidney diseases [38▪]. Finerenone treatment prevented deoxycorticosterone acetate/salt challenged rats from functional and structural heart and kidney damage at dosages which did not reduce systemic blood pressure. Furthermore, finerenone reduced cardiac hypertrophy, pro-B-type natriuretic peptide (BNP) and proteinuria more efficiently than eplerenone when comparing equi-natriuretic doses. Based on these preclinical investigations, it was speculated that finerenone might offer end organ protection with a reduced risk of electrolyte disturbances compared with steroidal MRAs in patients with chronic heart and kidney diseases [39]. Accordingly, finerenone was investigated in a clinical phase IIa study called ARTS among patients with chronic heart failure and concomitant CKD [14]. In these patients, once daily applications of 5 and 10 mg of finerenone were at least as effective as spironolactone 25 or 50 mg/day in decreasing BNP, NT-pro-BNP and urinary albumin, but it was associated with significantly lower increases in serum potassium, significantly lower incidences of hyperkalemia and lower incidence of worsening renal function [15]. ARTS-DN was a double-blind, placebo-controlled, parallel-group, multicenter phase IIb study in patients with diabetic nephropathy (T2DM and albuminuria ≥30 mg/g) receiving renin–angiotensin system (RAS) blockade [16]. Of 1501 patients screened at 148 sites, 823 were randomized to receive treatment. Addition of finerenone to standard of care resulted in dose-dependent, significant reductions in albuminuria at doses of 7.5, 10, 15 and 20 mg [17▪▪]. Hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10 mg groups; the incidence was 3.2% in the 15 mg group and 2.2% or less in all other groups. There were no differences in the incidence of eGFR decrease of 30% or more between the placebo and finerenone groups.

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The concept of developing drugs which may possess tissue-specific MRA activity has often been proposed [2,40,41▪,42], but the question remains – how and on which molecular mode of action will tissue-selective mineralocorticoid receptor antagonism ever become a reality? Data from the literature suggest that tissue selectivity could be achieved, at least theoretically, by addressing tissue-specific cofactors of mineralocorticoid receptor or by addressing cell-type specific signal cascades of mineralocorticoid receptor and its ligands aldosterone and cortisol. Remarkably, Shibata et al.[43] recently discovered that reversible (de)phosphorylation of serine 843 in the mineralocorticoid receptor ligand-binding domain regulates renal responses to volume depletion and hyperkalemia only via mineralocorticoid receptor expressed in intercalated cells of the distal nephron, strongly indicating a dominant role of this cell type during hyperkalemia. The groups of Fuller and Young used phage display and yeast-2-hybrid systems in order to identify tissue- and ligand-selective coregulators of mineralocorticoid receptor [40,41▪,42]. These groups identified at least four novel mineralocorticoid receptor coactivators, whose activity is dependent on the ligand (i.e. aldosterone or cortisol), cellular context and target gene promoter. They conclude that gene-specific recruitment of coregulators to mineralocorticoid receptor, combined with cell-specific ratios of coregulator expression, might ultimately determine the tissue-specific response to mineralocorticoid receptor ligands and that the unique sites of mineralocorticoid receptor–coregulator interaction might allow the identification of even more selective MRAs [41▪,42].

It is a remarkable observation that at least three nonsteroidal MRAs, SM-368229, PF-03882845 and finerenone, have demonstrated an improved therapeutic index (i.e. a more pronounced activity on either blood pressure reduction [SM-3868229], proteinuria reduction [PF-03882845 and finerenone] or cardiorenal end-organ protection [finerenone]) at doses which were adjusted to changes in electrolyte homeostasis such as serum potassium [SM-368229 and PF-03882845] or urinary sodium release [finerenone] compared with the steroidal MRAs spironolactone [with SM-368229] or eplerenone [compared with PF-03882845 or finerenone] in different preclinical animal studies.

The basis for the observed differences in the structural and functional cardiorenal protection of finerenone in comparison to eplerenone at equal natriuretic doses in preclinical models is a result of the fundamental differences in the chemical structure of the MRAs, i.e., steroidal and nonsteroidal scaffolds. The basic structure determines the physicochemical properties and the resulting pharmacological action dictates binding mode to mineralocorticoid receptor but also distribution in different tissues and recruitment or blockade of tissue-selective and ligand-specific cofactors [10]. Physicochemical drug properties have a strong impact on plasma protein binding, vascular transport, tissue penetration and distribution. Key physicochemical properties of a drug are the lipophilicity (estimated via the calculated logD) and the polarity (estimated via the polar surface area). Comparing the calculated logD values of steroidal and nonsteroidal MRAs reveals a much higher lipophilic character (six-fold to 10-fold) of the two steroidal compounds (Table 2). Moreover, there are also significant differences in the polar surface areas of the MRAs. Table 2 shows that finerenone exhibits greater polarity than the steroidal MRAs but also more than nonsteroidal PF-03882845. Molecules with a polar surface area value below 90 are generally capable of penetrating the blood–brain barrier and might therefore interfere with target proteins in the central nervous system. It is therefore important to note that centrally expressed MRs are believed to play a significant role in the control of blood pressure [44].

Figure 1 summarizes some key steps which may ultimately lead to pharmacodynamic differences between steroidal MRAs and the nonsteroidal MRA finerenone [45].



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Tissue distribution patterns differ significantly between mineralocorticoid receptor antagonists

The precise, time-dependent tissue distribution patterns of a drug can be visualized using quantitative whole-body autoradiography following the administration of radioactively labeled drug compounds. When analyzing finerenone distribution in healthy rats, we identified a balanced distribution into heart and kidney tissues [38▪]. This tissue distribution pattern is in clear contrast to the steroidal MRAs spironolactone and eplerenone. Experiments using radioactively labeled eplerenone demonstrated at least a three-fold higher accumulation of the drug equivalent concentration in the kidney compared with heart tissue in rats [46]. A similar study with radioactively labeled spironolactone revealed high drug concentrations within the kidneys, whereas radioactivity in heart tissue was below the detection limit [10]. Given these differences in physicochemical properties, one might expect further differences of the MRAs at the cellular level.

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Finerenone and steroidal mineralocorticoid receptor antagonists differ in their molecular receptor binding mode

We usually anticipate that a receptor blocker is a full antagonist. As mentioned herein, two groups have, however, reported at least some partial mineralocorticoid receptor agonistic activity of their nonsteroidal MRAs at higher concentrations [25,30]. Partial mineralocorticoid receptor agonism has also been described for spironolactone [40,47,48]. Massaad et al.[48] found that spironolactone might act as an agonist in a cell-specific and promoter-dependent manner. This group discovered that spironolactone had agonistic activity in hepatoma and renal epithelial cells while exerting its effect as a full antagonist in all other cell types studied. In contrast, dihydropyridine-based or naphthyridine-based nonsteroidal MRAs such as BR-4628 or finerenone exhibited full antagonism in a variety of different cell types in vitro[10,21,49].

Although BR-4628 and finerenone bind into the ligand binding domain of mineralocorticoid receptor, they exhibit a strikingly different accommodation mode in comparison to steroidal antagonists: finerenone and BR-4628 are so called ‘bulky’ antagonists [21,49]. Binding of ‘bulky’ nonsteroidal MRAs leads to a protrusion of helix 12 in the C-terminal activating function 2 domain of mineralocorticoid receptor. A comparable binding mode is known from other steroidal nuclear hormone receptor antagonists, mainly antiestrogens and antiprogestins, which carry bulky side-chains that do not hinder accommodation in the ligand binding niche, but prevent the helix 12 sterically assuming its activated conformation. This helix 12 protrusion constitutes an unstable receptor–ligand complex which is unable to recruit coregulators. The steroidal mineralocorticoid receptor antagonist eplerenone has been shown to stabilize the mineralocorticoid receptor in a transcriptionally inert conformation but does not actively recruit corepressors, possibly because of the fact that it has no influence on the conformation of helix 12 [50].

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Finerenone and eplerenone result in different myocardial gene expression patterns

In a mouse model of pressure-overload induced heart failure treatment with finerenone compared with eplerenone resulted in a more pronounced prevention of myocardial hypertrophy [51]. A possible explanation for the observed cardioprotection by finerenone in this study was a differential cardiac gene expression pattern in the hearts of animals treated either with finerenone or with eplerenone. The reduced myocardial hypertrophy might, therefore, result from altered myocardial gene regulation as a consequence of differential tissue distribution patterns and accordingly, tissue-specific mineralocorticoid receptor-cofactor modulation. The concept of tissue-selective modulation of a steroid receptor based on the chemical structure of the agent has originally been described for the estrogen receptor on the basis of the selective estrogen receptor modulators tamoxifen and raloxifene. Tissue-specific activities of these compounds have been attributed at least in part to their effects on tissue-specific coactivators [52].

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The nonsteroidal MRA finerenone has a unique pharmacodynamic profile which is considered to be a consequence of several individual key differences in comparison with steroidal MRAs including the physicochemical properties, tissue distribution, mode of mineralocorticoid receptor inactivation and differential regulation of downstream antihypertrophic gene expression. These different molecular properties of finerenone translate into different in-vivo properties with significant relevance for patients with cardiovascular diseases. Treatment of comorbid patients with heart and kidney diseases indicated a significantly better safety profile of finerenone compared with spironolactone.

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We thank Dr Lars Bärfacker (Medicinal Chemistry, Bayer Healthcare Pharmaceuticals) for providing logD values and topological PSA values and Dr Stuart Walsh for critical reading the manuscript.

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Financial support and sponsorship


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Conflicts of interest

All authors are full employees of Bayer Healthcare Pharmaceuticals.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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ARTS-DN was a double-blind, placebo-controlled, parallel-group, multicenter study in patients with diabetic nephropathy (T2DM and albuminuria ≥30 mg/g) receiving an ACE inhibitor or angiotensin receptor blocker and a serum potassium of at least 4.8 mmol/l at screening. Once-daily oral finerenone reduced albuminuria dose-dependently. Statistically significant differences in albuminuria reduction compared with placebo were observed with the four highest doses (7.5–20 mg once daily). The incidence of an eGFR decrease of at least 30% was not different between the placebo group and the finerenone groups. Hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10 mg groups; incidences in the finerenone 7.5, 15 and 20 mg groups were as low as 2.1, 3.2 and 1.7%, respectively.

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In this study, the authors carefully determined minimal effective doses of finerenone and eplerenone with respect to acute renal electrolyte effects (natriuresis) and to chronic end-organ protective effects. They found that finerenone reduced cardiac hypertrophy and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses.

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aldosterone; hyperkalemia; mode of action

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