Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Amazit, Larbi; Billan, Florian Le; Kolkhof, Peter; Lamribet, Khadija; Viengchareun, Say; Fay, Michèle; Khan, Junaid; Hillisch, Alexander; Lombès, Marc; Rafestin‐Oblin, Marie‐Edith; Fagart, Jérôme

doi:10.1074/jbc.m115.657957

Cited by 140 publications

(136 citation statements)

References 56 publications

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“…11 In addition, a gradual introduction in the highdose treatment groups was requested. Both requests made it necessary to set up a stand-alone study in Japan and not include Japanese patients in the globally conducted ARTS-HF study.…”

Section: Methodsmentioning

confidence: 99%

“…As this has been the first study to investigate finerenone in Japanese patients with HFrEF and CKD and/or diabetes, the PMDA requested to that the study design of ARTS-HF include additional mandatory visits in the first month of treatment in order to assure careful monitoring of serum potassium as was performed in the first global ARTS study. 11 This made it necessary to set up a stand-alone study in Japan. The design of ARTS-HF Japan is based on that of the international ARTS-HF, which was the first clinical trial to investigate the novel nonsteroidal MRA finerenone in comparison with eplerenone in patients with worsening HFrEF requiring emergency treatment and who also had T2DM and/or CKD.…”

Section: Role Of the Funding Sourcementioning

confidence: 99%

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A Randomized Controlled Study of Finerenone vs. Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease

Sato

Ajioka

Yamada

et al. 2016

Circ J

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on behalf of the ARTS-HF Japan study group Background: Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.Methods and Results: ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups. Conclusions:Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113 -1122

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Section: Methodsmentioning

confidence: 99%

Section: Role Of the Funding Sourcementioning

confidence: 99%

A Randomized Controlled Study of Finerenone vs. Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease

Sato

Ajioka

Yamada

et al. 2016

Circ J

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“…Chemical optimization of DHPs led to BR-4628, a bulky antagonist that occupied the MR ligand-binding domain different from spironolactone, resulting in an extremely unstable complex that is unable to recruit transcriptional co-regulators [32,33]. Further researches on high through put screening and structure activity relationship exploration led to the identification of a dihydroanphthyridine, finerenone [15].…”

Section: Finerenone: a Novel Nonsteroidal Mrasmentioning

confidence: 97%

The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: Progress and challenges

Yang

Huang

2016

Metabolism

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“…Despite the clear benefits of MRAs for the treatment of heart failure, a better understanding of the underlying mechanisms that account for these beneficial effects is still lacking. Of note, the non-steroidal MRA finerenone has recently been shown to prevent full nuclear import of MR, and inhibit MR and coactivator binding to genomic target genes (Amazit et al 2015). Moreover, concerns about elevated potassium resorption with the use of current MRAs remain a key reason for their limited use in the clinic.…”

Section: The Adrenal Corticosteroids Mr Signalling In Cells and Mr Amentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

Cole

Young

2017

Journal of Endocrinology

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The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone. Generation of tissue-selective MR-deficient mice using Cre recombinase-LoxP gene targeting has made it possible to analyse mice lacking MR only in specific cell types. Targeting renal-specific MR has differentiated roles in specific compartments of the kidney. Ablating MR in neurons of the forebrain reinforced important roles of the MR in response to stress, behaviour and anxiety, but suggested a minimal role in maintaining basal HPA axis tone. Deletion of the MR in macrophages and other cell types of the cardiovascular system clearly defined important roles for the regulation of cardiovascular physiology and pathophysiology. Knockdown of MR mRNA in vivo using antisense/siRNA approaches, and similarly MR overexpression, has provided useful rodent models to study physiological roles of MR signalling in vivo. More recently, targeted mutation of specific domains of the MR such as the DBD has defined genomic vs non-genomic roles in vivo. New tissue-selective MR-null models are required to define roles of MR signalling in other regions of the brain, the eye, gastrointestinal tract, lung, skin, breast and gonadal organs.

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Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Cited by 140 publications

References 56 publications

A Randomized Controlled Study of Finerenone vs. Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease

A Randomized Controlled Study of Finerenone vs. Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease

The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: Progress and challenges

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor null mice: informing cell-type-specific roles

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