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Review
. 2017 Jul;234(1):T125-T140.
doi: 10.1530/JOE-16-0600.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Peter Kolkhof  1 , Lars Bärfacker  2
Affiliations
Review

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Peter Kolkhof et al. J Endocrinol. 2017 Jul.

Abstract

The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs.

Keywords: apararenone; canrenone; eplerenone; esaxerenone; finerenone; mineralocorticoid receptor antagonists; potassium canrenoate; spironolactone.

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Figures

Figure 1
Figure 1
Important steroidal MRAs. Chemical structures of the most important 17-spirolactone derivatives, which were discovered and published between 1957 (beginning on top of the figure) and 1987 are shown. Launched drug compounds are highlighted by a white background. Open-ring potassium salt derivatives are highlighted by a light grey background (note that potassium canrenoate is both, a launched drug and a potassium salt derivative). Active metabolites are highlighted by a darker grey background. Arrows indicate either the generation of respective active metabolites from spironolactone (to different quantitative amounts, indicated by respective arrow sizes) or the equilibrium of the open-ring potassium salts with the respective lactone metabolite. Note the structural similarities of several stacked derivatives, e.g. mexrenone and eplerenone, or spironolactone and mespirenone.
Figure 2
Figure 2
Novel non-steroidal MRAs in clinical development. Chemical structures of the three clinically most advanced non-steroidal MRAs apararenone, esaxerenone and finerenone are shown (from left to right).
Figure 3
Figure 3
60 years of research and development on MRAs. The time bar highlights relevant publications on the discovery of MRAs or important clinical trial results with MRAs (RALES, EPHESUS, EMPHASIS-HF, ARTS, ARTS-DN and ARTS-HF) in a given year. Note that cloning of MR was at midway within the 60 years of R&D on MRAs.
See this image and copyright information in PMC

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