STRUCTURE:(−)-Finerenone is a nonsteroidal selective mineralocorticoid receptor (MR) antagonist. The core 1,6-naphthyridine core in red; (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-didydro-1,6-naphthyridine (core in red)-3-carboxamide.
NAME:
Finerenone, brand name is Kerendia®.
DRUG CLASS:
Nonsteroidal, selective MR antagonist.
CLINICAL USE:
Finerenone is indicated to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D).
DEVELOPED BY:
Bayer Healthcare.
ADVERSE EFFECTS:
Hyperkalemia, hypotension, hyponatremia.
TIMELINE:
2012, finerenone (BAY 94-8862) was described as a potent, selective, orally available nonsteroidal mineralocorticoid receptor antagonist discovered by high-throughput screening
2012–2021, finerenone was investigated in the clinical Phase 2 ‘ARTS-DN’ trial (NCT01874431) in subjects with T2D and the clinical diagnosis of diabetic nephropathy and in patients with chronic heart failure with renal impairment (NCT01345656). Since 2013, finerenone has been investigated in a broad population of patients with stages 1–4 CKD and T2D (NCT0187443, NCT01955694, NCT01968668), and across two completed and published Phase 3 studies, FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), that evaluated the effects of finerenone versus placebo on top of standard of care on both renal and cardiovascular outcomes in patients with CKD and T2D
July 9, 2021, US FDA approved finerenone (Kerendia®).
MECHANISM OF ACTION:
The MR is a ligand-controlled transcription factor expressed in the heart, vasculature, and kidneys, among other tissues. In the diabetic milieu, chronic MR activation promotes expression of profibrotic and inflammatory genes and activation of signaling pathways implicated in kidney and cardiovascular disease progression. In the kidney, chronic MR overactivation in different glomerular, tubular, and vascular renal cell types results in fibrosis, proteinuria, impaired kidney function, and eventually end-stage kidney failure. In the heart, MR overactivation is associated with cardiovascular death and morbidity. Aldosterone, a mineralocorticoid steroid hormone that plays a central role in the homeostatic regulation of blood pressure, plasma sodium, and potassium ion levels, acts via intracellular MR. Elevated aldosterone release and high salt load increase the generation of reactive oxygen species (ROS), hemodynamic factors, or inflammatory and fibrotic factors driving MR overactivation. Finerenone has been shown to block the harmful effects of MR overactivation by aldosterone. Finerenone, considered a bulky MR antagonist, may cause a protrusion or conformational change of helix 12–critical for recruitment of transcriptional cofactor SRC-1 on the promoter of MR target genes–in the C-terminal domain of MR. Inhibition of MR coactivator binding may occur also in the absence of aldosterone. In the heart and vasculature, finerenone has been shown to improve coronary vasodilation and left ventricle perfusion and to reduce collagen deposition. In the kidney, antagonism of MR with finerenone substantially ameliorates glomerular damage, reducing proteinuria and tubulointerstitial fibrosis. Finerenone was shown to decrease pathological myofibroblast accumulation, restore vascular integrity, and improve endothelial dysfunction via enhancing nitric oxide bioavailability and decreasing ROS levels in experimental models of kidney disease.
February 21, 2022, the European Commission granted marketing authorization in the EU for finerenone (Kerendia®).
Acknowledgments
This work was supported by National Institutes of Health grant R01DK097253 and Department of Defense CDMRP grant E01 W81XWH2010836 to I.S.D. and by National Institutes of Health grants R01AI132614-01A1, R21 AA027374-01, and 1R01NS109423-01A1 to B.D. Figure created with BioRender.com.
Footnotes
Declaration of interests
The authors have no interests to declare.
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