CURRENT OPINION Nonsteroidal Antagonists of the Mineralocorticoid Receptor

REVIEW

CURRENT OPINION Nonsteroidal antagonists of the mineralocorticoid receptor

Peter Kolkhof a, Christina Nowackb, and Frank Eitner a

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. Keywords aldosterone, hyperkalemia, mode of action

INTRODUCTION reported in up to 36% among unselected elderly Pathological overactivation of the mineralocorti- heart failure outpatients with about 10% developing coid receptor plays a critical and causative role in potential life-threatening serum potassium levels of the pathogenesis of a variety of different cardiovas- greater than 6 mmol/l [7,8]. cular diseases [1&&,2,3]. Accordingly, blockade of Consequently, drug discovery programs within mineralocorticoid receptor has proven clinical effi- several pharmaceutical companies are aiming to cacy in patients with heart failure with reduced identify novel nonsteroidal MRAs with potentially ejection fraction, arterial hypertension and chronic different pharmacodynamic properties. Recent kidney diseases (CKD) [1&&,4&,5&]. Current attempts reviews have already addressed some aspects of to block aldosterone’s action at the mineralocorticoid receptor by using the available steroidal mineralocorticoid receptor antagonists (MRAs) spi- aGlobal Drug Discovery, Cardiology Research and bGlobal Clinical ronolactone or eplerenone might, however, cause a Development, Bayer Healthcare Pharmaceuticals, Wuppertal, Germany dilemma for the responsible physician; although Correspondence to Dr Peter Kolkhof, Cardiology Research, Bayer these drugs could be a life-saving therapy for Healthcare Pharmaceuticals, Building 500, Aprather Weg 18a, 42096 Wuppertal, Germany. Tel: +49 202365475; fax: +49 202368009; patients with heart failure [6], they may also induce e-mail: [email protected] severe hyperkalemia and kidney dysfunction, Curr Opin Nephrol Hypertens 2015, 24:417–424 particularly when given on top of standard of care DOI:10.1097/MNH.0000000000000147 angiotensin converting enzyme inhibitors or angio- This is an open-access article distributed under the terms of the Creative tensin receptor blockers to ‘real life’ patients, typi- Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where cally with variable degrees of concomitant kidney it is permissible to download and share the work provided it is properly dysfunction. In fact, hyperkalemic episodes were cited. The work cannot be changed in any way or used commercially.

whereas treatment with spironolactone decreased KEY POINTS blood pressure at doses of 100 and 300 mg/kg with The broad clinical use of steroidal MRAs spironolactone concomitant elevation of serum potassium at and eplerenone is limited by the potential risk of 300 mg/kg [27]. These results may suggest an inducing hyperkalemia when given on top of improved therapeutic index of SM-368229 in com- RAS blockade. parison to spironolactone. To date, no clinical study has, however, been announced for SM-368229. Very Novel, nonsteroidal MRAs are currently being & developed to overcome such limitations. recently, Nariai et al. [28 ] presented preclinical data of another Dainippon Sumitomo MRA called DSR- Nonsteroidal finerenone has different physicochemical 71167, which also weakly blocks carbonic anhydrase. and tissue distribution properties compared with DSR-71167, in contrast to spironolactone and epler- steroidal eplerenone or spironolactone. enone, did not cause elevation of serum potassium Finerenone demonstrated superior safety and efficacy levels in potassium-loaded rats. Carbonic anhydrase compared with spironolactone in patients with heart inhibition may increase urinary potassium and there- failure and CKD. fore 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 these efforts [9–12,13&]. This review will serve two [29–31]. Initially, selected lead compounds still key purposes: first, it provides a current overview of had moderate affinity at the progesterone receptor, preclinical and clinical studies using nonsteroidal whereas related dihydropyrrol-2-one derivatives MRAs with a particular focus on recent clinical trials, exhibited moderate and partial mineralocorticoid and second, it summarizes our current knowledge of receptor agonistic activity at higher concentrations differences in the mode of action between steroidal (30% activation at 10 mM). A novel, benzoxazin-3- MRAs and the novel, nonsteroidal MRA finerenone. one derivative has recently been presented which significantly lowered the blood pressure of deoxycorticosterone acetate/salt hypertensive rats after PRECLINICAL AND CLINICAL ACTIVITIES oral application [31]. REPORTED ON NONSTEROIDAL LY2623091 (Eli Lilly, Table 1) entered clinical MINERALOCORTICOID RECEPTOR phase I trials in October 2010 and has been inves- ANTAGONISTS tigated in a small phase IIa trial in 48 patients with Table 1 summarizes the current landscape of non- CKD until March 2013. Recently, Lilly announced steroidal MRAs in clinical development [14–18]. At the start of a larger phase II trial, this time, however, least five pharmaceutical companies have novel, among 300 hypertensive patients, which may nonsteroidal MRAs in clinical study development indicate a refocussing of this nonsteroidal MRA (source: clinicaltrials.gov) with a clear focus on the on the therapy of arterial hypertension. Lilly has treatment of patients with CKD. Additional com- also investigated LY3045697 in two small phase I pounds are in preclinical development [13&]. The studies in healthy volunteers during 2013 in The chemical structures have only been revealed for two Netherlands. No published data on these novel compounds under clinical development (Table 2) MRAs are available. [19,20]: Bayer’s finerenone [21] and Pfizer’s PF- Mitsubishi is currently conducting its nonster- 03882845 [22]; however, more structural infor- oidal MRA MT-3995 in small phase IIa studies in mation is available for pharmaceutical compounds Japan and two studies in Eastern Europe (n ¼ 30–90) in preclinical studies. among patients with diabetic nephropathy [32] Researchers at Merck identified oxazolidine- (Table 1). dione derivatives as novel, nonsteroidal MRAs CS-3150 is a novel, nonsteroidal MRA which was [23,24]. Representative compounds demonstrated discovered by Exelixis and out-licensed to Daiichi- acceptable in-vitro potency and selectivity but Sankyo in 2006. In January 2015, Daiichi-Sankyo no pharmacodynamic in-vivo data have been announced the start of two different phase II studies: published. a dose-finding study in Japanese patients with Dainippon Sumitomo discovered the nonsteroi- T2DM and microalbuminuria [33] and a study to dal MRA SM-368229, possessing moderate selectivity evaluate efficacy and safety of CS-3150 in Japanese towards other steroid receptors [25,26]. In spon- patients with hypertension (estimated enrollment: taneously hypertensive rats, SM-368229 decreased 400 patients) [34] (Table 1). systolic blood pressure at doses between 1 and Pfizer investigated the nonsteroidal MRA PF- 10 mg/kg without serum potassium elevation, 03882845 (Tables 1 and 2) in preclinical as well in

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Table 1. Current landscape of clinical trials with nonsteroidal mineralocorticoid receptor antagonists (source: clinicaltrials.gov)

NCT# Phase Condition/study name No. enrolled Study begin Study completion Status/references

Finerenone NCT01473108 1 Healthy 67 Mar 2010 Nov 2010 Completed NCT01687920 1 Healthy 25 Sep 2012 Nov 2012 Completed NCT01345656 2a ARTS 457 May 2011 Jun 2012 Completed [14,15] NCT01968668 2b ARTS-DN (J) 96 Oct 2013 Nov 2014 Completed NCT01955694 2b ARTS-HF (J) 66 Oct 2013 Feb 2015 Completed NCT01874431 2b ARTS-DN 670 Jun 2013 Sep 2014 Completed [16,17&&] NCT01807221 2b ARTS-HF 1060 Jun 2013 Jan 2015 Completed [18] CS-3150 NCT02345057 2 DN (J) 325 Jan 2015 Mar 2017 Recruiting NCT02345044 2 HT (J) 400 Jan 2015 Jun 2016 Recruiting LY2623091 NCT01237899 1 Healthy 32 Oct 2010 Jan 2011 Completed NCT01427972 2a CKD 48 Sep 2011 Mar 2013 Completed NCT02242981 1 Healthy 6 Sep 2014 Nov 2014 Completed NCT02194465 2a HT 300 Aug 2014 April 2015 Recruiting NCT02300259 1 Healthy 48 Nov 2014 Mar 2015 Not recruiting MT-3995 NCT01756703 2 DN 90 Nov 2012 Nov 2014 Not recruiting NCT01756716 2 DN 90 Dec 2012 Jan 2015 Not recruiting NCT01889277 2 DN (J) 45 July 2013 Jan 2015 Not recruiting NCT02205372 2 DN (J) 30 July 2014 Aug 2015 Recruiting PF-03882845 NCT00856258 1 Healthy 10 Mar 2009 Jun 2009 Terminated NCT00971802 1 Healthy 50 Sep 2009 Feb 2010 Completed NCT01366287 1 Healthy 12 Jan 2011 Feb 2011 Completed NCT01314898 1 Healthy 12 Mar 2011 Jun 2011 Completed NCT01445860 1 Healthy 14 Aug 2011 Sep 2011 Completed NCT01488877 1b T2 DN 6 Jan 2012 Jul 2012 Terminated

ARTS, MinerAlocorticoid Receptor Antagonist Tolerability Study; CKD, chronic kidney disease; DN, diabetic nephropathy; HF, heart failure; HT, hypertension; J, local study in Japan; NCT, number of clinical trial; T2 DN, Type 2 diabetes mellitus diabetic nephropathy. The numbers in brackets in the last column refer to the published clinical studies.

Table 2. Key physicochemical properties of steroidal and nonsteroidal mineralocorticoid receptor antagonists

Spironolactone Eplerenone PF-03882845 Finerenone

N O O O O H O N N Chemical structure H H N O O CI O S O O OO O O CH H2N N N H

Calculated logDa (lipophilicity) 3.13 3.03 2.07 2.40 Topological PSAb (polarity) 60.4 82.2 76.7 110.3 aThe lipophilicity of a drug compound can be estimated via calculating the logD value and was calculated on the basis of [19]. Higher logD values indicatea higher lipophilic character of the drug. bThe polar surface area (PSA) is an indicator for the polarity of a drug compound and was calculated on the basis of [20]. The polarity of a drug affects also its tissue distribution properties. Higher PSA values indicate a higher polarity of the drug.

1062-4821 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-nephrolhypertens.com 419 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pharmacology and therapeutics several clinical phase I studies. This compound serum potassium, significantly lower incidences of was characterized as potent and selective MRA hyperkalemia and lower incidence of worsening in vitro, which demonstrated a striking reduction renal function [15]. ARTS-DN was a double-blind, of blood pressure and improved renal protection in placebo-controlled, parallel-group, multicenter comparison to eplerenone in a preclinical model of phase IIb study in patients with diabetic nephrop- salt-induced hypertension and nephropathy [22]. athy (T2DM and albuminuria 30 mg/g) receiving Orena et al. [35] determined the respective plasma renin–angiotensin system (RAS) blockade [16]. drug concentrations of eplerenone and PF- Of 1501 patients screened at 148 sites, 823 were 03882845 that were necessary to decrease urinary randomized to receive treatment. Addition of albumin and to increase serum potassium in a rat finerenone to standard of care resulted in dose- kidney injury model and calculated a therapeutic dependent, significant reductions in albuminuria index, i.e., the ratio of the half maximal effective at doses of 7.5, 10, 15 and 20 mg [17&&]. Hyperkale- concentration (EC50) for increasing serum potass- mia leading to discontinuation was not observed in ium to the respective EC50 for urinary albumin the placebo and finerenone 10 mg groups; the inci- lowering. This ratio was 1.47 for eplerenone and dence was 3.2% in the 15 mg group and 2.2% or less 83.8 for PF-03882845. The compound was advanced in all other groups. There were no differences in the to clinical phase I in 2009, to a multiple dose appli- incidence of eGFR decrease of 30% or more between cation trial in healthy volunteers that was, however, the placebo and finerenone groups. terminated based on safety concerns (clinicaltrials.- gov NCT00856258). Several further phase I trials with PF-03882845 have been conducted up to DIFFERENCES IN THE MODE OF ACTION 2012 (Table 1). The last study (NCT01488877) BETWEEN STEROIDAL was, however, terminated in July 2012, reportedly MINERALOCORTICOID RECEPTOR ‘for strategic reasons’. Recently, Pfizer published the ANTAGONISTS AND THE NOVEL, chemical structures of possible back-up compounds NONSTEROIDAL MINERALOCORTICOID of PF-03882845 [36] including a new class of aryl RECEPTOR ANTAGONIST FINERENONE sulfonamide-based nonsteroidal MRAs [37]. The concept of developing drugs which may possess The compound that is currently most advanced tissue-specific MRA activity has often been proposed in clinical development is Bayer’s finerenone which [2,40,41&,42], but the question remains – how and has, up to today, been investigated in more than on which molecular mode of action will tissue- 2000 patients in a phase IIa (ARTS [14,15]) and two selective mineralocorticoid receptor antagonism phase IIb trials (ARTS-DN [16,17&&] and ARTS-HF ever become a reality? Data from the literature [18]) (Tables 1 and 2). Finerenone has been inves- suggest that tissue selectivity could be achieved, at tigated in different preclinical animal models of least theoretically, by addressing tissue-specific chronic hypertensive and ischemic heart and kidney cofactors of mineralocorticoid receptor or by diseases [38&]. Finerenone treatment prevented addressing cell-type specific signal cascades of min- deoxycorticosterone acetate/salt challenged rats eralocorticoid receptor and its ligands aldosterone from functional and structural heart and kidney and cortisol. Remarkably, Shibata et al. [43] recently damage at dosages which did not reduce systemic discovered that reversible (de)phosphorylation of blood pressure. Furthermore, finerenone reduced serine 843 in the mineralocorticoid receptor cardiac hypertrophy, pro-B-type natriuretic peptide ligand-binding domain regulates renal responses (BNP) and proteinuria more efficiently than epler- to volume depletion and hyperkalemia only via enone when comparing equi-natriuretic doses. mineralocorticoid receptor expressed in intercalated Based on these preclinical investigations, it was cells of the distal nephron, strongly indicating a speculated that finerenone might offer end organ dominant role of this cell type during hyperkalemia. protection with a reduced risk of electrolyte disturb- The groups of Fuller and Young used phage display ances compared with steroidal MRAs in patients and yeast-2-hybrid systems in order to identify with chronic heart and kidney diseases [39]. Accord- tissue- and ligand-selective coregulators of minera- ingly, finerenone was investigated in a clinical locorticoid receptor [40,41&,42]. These groups ident- phase IIa study called ARTS among patients with ified at least four novel mineralocorticoid receptor chronic heart failure and concomitant CKD [14]. In coactivators, whose activity is dependent on the these patients, once daily applications of 5 and ligand (i.e. aldosterone or cortisol), cellular context 10 mg of finerenone were at least as effective as and target gene promoter. They conclude that gene- spironolactone 25 or 50 mg/day in decreasing specific recruitment of coregulators to mineralocor- BNP, NT-pro-BNP and urinary albumin, but it was ticoid receptor, combined with cell-specific ratios of associated with significantly lower increases in coregulator expression, might ultimately determine

420 www.co-nephrolhypertens.com Volume 24 Number 5 September 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nonsteroidal antagonists of the mineralocorticoid receptor Kolkhof et al. the tissue-specific response to mineralocorticoid Tissue distribution patterns differ receptor ligands and that the unique sites of min- significantly between mineralocorticoid eralocorticoid receptor–coregulator interaction receptor antagonists might allow the identification of even more selec- The precise, time-dependent tissue distribution pat- tive MRAs [41&,42]. terns of a drug can be visualized using quantitative It is a remarkable observation that at least three whole-body autoradiography following the admin- nonsteroidal MRAs, SM-368229, PF-03882845 and istration of radioactively labeled drug compounds. finerenone, have demonstrated an improved When analyzing finerenone distribution in healthy therapeutic index (i.e. a more pronounced activity rats, we identified a balanced distribution into heart on either blood pressure reduction [SM-3868229], and kidney tissues [38&]. This tissue distribution proteinuria reduction [PF-03882845 and finere- pattern is in clear contrast to the steroidal MRAs none] or cardiorenal end-organ protection [finer- spironolactone and eplerenone. Experiments using enone]) at doses which were adjusted to changes radioactively labeled eplerenone demonstrated at in electrolyte homeostasis such as serum potas- least a three-fold higher accumulation of the drug sium [SM-368229 and PF-03882845] or urinary equivalent concentration in the kidney compared sodium release [finerenone] compared with the with heart tissue in rats [46]. A similar study with steroidal MRAs spironolactone [with SM-368229] radioactively labeled spironolactone revealed high or eplerenone [compared with PF-03882845 drug concentrations within the kidneys, whereas or finerenone] in different preclinical animal radioactivity in heart tissue was below the detection studies. limit [10]. Given these differences in physicochem- The basis for the observed differences in the struc- ical properties, one might expect further differences tural and functional cardiorenal protection of finer- of the MRAs at the cellular level. enone in comparison to eplerenone at equal natriuretic doses in preclinical models is a result of Finerenone and steroidal mineralocorticoid the fundamental differences in the chemical structure receptor antagonists differ in their molecular of the MRAs, i.e., steroidal and nonsteroidal scaffolds. receptor binding mode The basic structure determines the physicochemical We usually anticipate that a receptor blocker is a full properties and the resulting pharmacological action antagonist. As mentioned herein, two groups have, dictates binding mode to mineralocorticoid receptor however, reported at least some partial mineralo- but also distribution in different tissues and recruit- corticoid receptor agonistic activity of their non- ment or blockade of tissue-selective and ligand- steroidal MRAs at higher concentrations [25,30]. specific cofactors [10]. Physicochemical drug proper- Partial mineralocorticoid receptor agonism has also ties have a strong impact on plasma protein binding, been described for spironolactone [40,47,48]. Mas- vascular transport, tissue penetration and distri- saad et al. [48] found that spironolactone might act bution. Key physicochemical properties of a drug as an agonist in a cell-specific and promoter-depend- are the lipophilicity (estimated via the calculated ent manner. This group discovered that spironolac- logD) and the polarity (estimated via the polar surface tone had agonistic activity in hepatoma and renal area). Comparing the calculated logD values of epithelial cells while exerting its effect as a full steroidal and nonsteroidal MRAs reveals a much antagonist in all other cell types studied. In contrast, higher lipophilic character (six-fold to 10-fold) of dihydropyridine-based or naphthyridine-based the two steroidal compounds (Table 2). Moreover, nonsteroidal MRAs such as BR-4628 or finerenone there are also significant differences in the polar sur- exhibited full antagonism in a variety of different face areas of the MRAs. Table 2 shows that finerenone cell types in vitro [10,21,49]. exhibits greater polarity than the steroidal MRAs but Although BR-4628 and finerenone bind into also more than nonsteroidal PF-03882845. Molecules the ligand binding domain of mineralocorticoid with a polar surface area value below 90 are generally receptor, they exhibit a strikingly different acco- capable of penetrating the blood–brain barrier and mmodation mode in comparison to steroidal might therefore interfere with target proteins in the antagonists: finerenone and BR-4628 are so called central nervous system. It is therefore important to ‘bulky’ antagonists [21,49]. Binding of ‘bulky’ non- note that centrally expressed MRs are believed to play steroidal MRAs leads to a protrusion of helix 12 in a significant role in the control of blood pressure the C-terminal activating function 2 domain of [44]. mineralocorticoid receptor. A comparable binding Figure 1 summarizes some key steps which may mode is known from other steroidal nuclear hor- ultimately lead to pharmacodynamic differences mone receptor antagonists, mainly antiestrogens between steroidal MRAs and the nonsteroidal and antiprogestins, which carry bulky side-chains MRA finerenone [45]. that do not hinder accommodation in the ligand

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Steroidal MR agonist/antagonists Non-steroidal MR antagonist

aldosterone spironolactone eplerenone finerenone agonist antagonists Physicochemical properties 1 Tissue distribution / cellular penetration

Finerenone

Eplerenone Binding mode MR MR 2 MR translocation / Degradation

Spironolactone MR

Coregulator modulation 3 Differential gene expression MR Aldosterone MR

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]. binding niche, but prevent the helix 12 sterically animals treated either with finerenone or with epler- assuming its activated conformation. This helix 12 enone. The reduced myocardial hypertrophy might, protrusion constitutes an unstable receptor–ligand therefore, result from altered myocardial gene regu- complex which is unable to recruit coregulators. The lation as a consequence of differential tissue distri- steroidal mineralocorticoid receptor antagonist bution patterns and accordingly, tissue-specific eplerenone has been shown to stabilize the miner- mineralocorticoid receptor-cofactor modulation. alocorticoid receptor in a transcriptionally inert The concept of tissue-selective modulation of a conformation but does not actively recruit corepres- steroid receptor based on the chemical structure sors, possibly because of the fact that it has no of the agent has originally been described for the influence on the conformation of helix 12 [50]. estrogen receptor on the basis of the selective estrogen receptor modulators tamoxifen and raloxifene. Finerenone and eplerenone result in different Tissue-specific activities of these compounds have myocardial gene expression patterns been attributed at least in part to their effects on In a mouse model of pressure-overload induced tissue-specific coactivators [52]. heart failure treatment with finerenone compared with eplerenone resulted in a more pronounced CONCLUSION prevention of myocardial hypertrophy [51]. A The nonsteroidal MRA finerenone has a unique possible explanation for the observed cardioprotec- pharmacodynamic profile which is considered to tion by finerenone in this study was a differential be a consequence of several individual key differ- cardiac gene expression pattern in the hearts of ences in comparison with steroidal MRAs including

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11. Tamargo J, Solini A, Ruilope LM. Comparison of agents that affect aldosterone the physicochemical properties, tissue distribution, action. Semin Nephrol 2014; 34:285–306. mode of mineralocorticoid receptor inactivation 12. Luther JM. Is there a new dawn for selective mineralocorticoid receptor antagonism? Curr Opin Nephrol Hypertens 2014; 23:456–461. and differential regulation of downstream antihy- 13. Collin M, Niemann F, Jaisser F. Mineralocorticoid receptor modulators: a pertrophic gene expression. These different molecu- & patent review (2007–2012). Expert Opin Ther Pat 2014; 24:177–183. In this review article, the authors give a comprehensive overview of patents on MRA lar properties of finerenone translate into different modulators which were published between the years 2007 and 2012. The authors in-vivo properties with significant relevance for conclude that novel nonsteroidal MRAs with particular pharmacokinetic profiles may avoid the undesirable renal side-effects of steroidal MRAs. These so-called patients with cardiovascular diseases. Treatment ‘kidney friendly MRAs’ are expected to become a clear breakthrough in the field. of comorbid patients with heart and kidney diseases 14. Pitt B, Filippatos G, Gheorghiade M, et al. Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic indicated a significantly better safety profile of finer- heart failure and mild or moderate chronic kidney disease. Eur J Heart Fail enone compared with spironolactone. 2012; 14:668–6675. 15. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel nonsteroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients Acknowledgements with chronic heart failure and mild or moderate chronic kidney disease: a We thank Dr Lars Ba¨rfacker (Medicinal Chemistry, randomized, double-blind trial. Eur Heart J 2013; 34:2453–2463. 16. Ruilope LM, Agarwal R, Chan JC, et al. Rationale design, and baseline Bayer Healthcare Pharmaceuticals) for providing logD characteristics of ARTS-DN: a randomized study to assess the safety and values and topological PSA values and Dr Stuart Walsh efficacy of finerenone in patients with type 2 diabetes mellitus and a clinical diagnosis of diabetic nephropathy. Am J Nephrol 2014; 40:572–581. for critical reading the manuscript. 17. Bakris GL, Nowack C, Ruilope LM. Results of ARTS-DN: a randomized study && to assess the safety and efficacy of finerenone in patients with type 2 diabetes Financial support and sponsorship and diabetic nephropathy. In: World Congress of Nephrology 2015, 13–17 March 2015, Cape Town, South Africa http://www.abstracts2view.com/wcn/ None. view.php?nu=WCN15L_SUN-488&terms=. [Accessed 20 May 2015] ARTS-DN was a double-blind, placebo-controlled, parallel-group, multicenter Conflicts of interest study in patients with diabetic nephropathy (T2DM and albuminuria 30 mg/g) receiving an ACE inhibitor or angiotensin receptor blocker and a serum potassium All authors are full employees of Bayer Healthcare Phar- of at least 4.8 mmol/l at screening. Once-daily oral finerenone reduced albuminuria dose-dependently. Statistically significant differences in albuminuria reduction maceuticals. 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. 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