title: Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury.
abstract: Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.
authors.affiliation: Institutes of *Cardiology Research; †Clinical Sciences; ‡Drug Metabolism and Pharmacokinetics; §Toxicology; and ¶Medicinal Chemistry, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.forename: Martina
authors.initials: M
authors.lastname: Delbeck
authors.forename: Axel
authors.initials: A
authors.lastname: Kretschmer
authors.forename: Wolfram
authors.initials: W
authors.lastname: Steinke
authors.forename: Elke
authors.initials: E
authors.lastname: Hartmann
authors.forename: Lars
authors.initials: L
authors.lastname: Bärfacker
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.forename: Barbara
authors.initials: B
authors.lastname: Albrecht-Küpper
authors.forename: Stefan
authors.initials: S
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D001345:Autoradiography; D006332:Cardiomegaly / Q000517:prevention & control; D004195:Disease Models, Animal; D000077545:Eplerenone; D006333:Heart Failure / Q000517:prevention & control*; D007674:Kidney Diseases / Q000517:prevention & control*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D009287:Naphthyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; D010446:Peptide Fragments; C576501:finerenone; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D013148:Spironolactone; D000077545:Eplerenone