INTRODUCTION
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.
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Box 1: no caption available
PRECLINICAL AND CLINICAL ACTIVITIES REPORTED ON NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS
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: clinicaltrials.gov) 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: Current landscape of clinical trials with nonsteroidal mineralocorticoid receptor antagonists (source: clinicaltrials.gov)
Table 2: Key physicochemical properties of steroidal and nonsteroidal mineralocorticoid receptor antagonists
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.[28â–ª] 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 (clinicaltrials.gov 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.
DIFFERENCES IN THE MODE OF ACTION BETWEEN STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS AND THE NOVEL, NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST FINERENONE
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].
FIGURE 1: Differential modes of action between the steroidal MRAs and the nonsteroidal finerenone. The steroidal mineralocorticoid receptor agonist (aldosterone) and antagonists (spironolactone and eplerenone) are structurally distinct from the nonsteroidal MRA finerenone, as shown at the top of the figure. The key cellular localizations, which determine the final pharmacological profile of steroidal MRAs and finerenone, are as follows: first, the extracellular space and plasma membrane (determination of tissue distribution and cellular penetration), second, the cytoplasm (binding mode determines the nuclear translocation of mineralocorticoid receptor or its degradation) and third, the nucleus (ligand-dependent coregulator modulation determines differential gene expression). The three-dimensional structures of aldosterone, spironolactone, eplerenone and finerenone were used for a schematic visualization of intracellular ligand binding to mineralocorticoid receptor in order to highlight the fundamental differential binding modes of ‘flat’ steroidal structures and ‘bulky’ finerenone. Only one mineralocorticoid receptor monomer bound to finerenone has been depicted in the nucleus of this figure. The three-dimensional structures have been generated with PubChem3D
[45].
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 [38â–ª]. 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.
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].
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].
CONCLUSION
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.
Acknowledgements
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.
Financial support and sponsorship
None.
Conflicts of interest
All authors are full employees of Bayer Healthcare Pharmaceuticals.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- â–ª of special interest
- ▪▪ of outstanding interest
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