The Time to Reconsider Mineralocorticoid Receptor Blocking Strategy: Arrival of Nonsteroidal Mineralocorticoid Receptor Blockers

Abstract

Purpose of review: The study aims to verify the advantages of nonsteroidal mineralocorticoid receptor blockers (MRBs) in the management of hypertension and cardiovascular and renal diseases, comparing with conventional MRBs.

Recent findings: Based on the unique structures, the nonsteroidal MRBs have higher selectivity for mineralocorticoid receptors (MRs) and show no agonist activity for major steroid hormone receptors in contrast to steroidal MRBs. Today, there are two nonsteroidal MRBs, esaxerenone and finerenone, which completed phase 3 clinical trials. Series of clinical trials have shown that both agents achieve similar MR blockade with smaller doses as compared with steroidal MRBs, but have no off-target side effect such as gynecomastia. Esaxerenone has persistent blood pressure-lowering effects in various hypertensive populations, including essential hypertension and those with diabetes and/or chronic kidney disease, while finerenone has demonstrated reduction of the cardiovascular risk rather than blood pressure in patients with diabetes and chronic kidney disease. Nonsteroidal MRBs are a more refined agent which contributes to appropriate MR blocking with minimized unpleasant adverse effects.

Keywords: Esaxerenone; Finerenone; Hypertension; Mineralocorticoid receptor; Nonsteroidal mineralocorticoid receptor blocker.

Fig. 1

Molecular structures of steroids and mineralocorticoid receptor blockers. The structures of steroidal and nonsteroidal mineralocorticoid receptor blockers (MRBs) are shown, compared with aldosterone, a representative mineralocorticoid in human, and progesterone. Spironolactone was generated by mimicking the structure of progesterone, while eplerenone was developed to improve the selectivity of spironolactone for mineralocorticoid receptors. Nonsteroidal MRBs are relatively “bulky” and quite distinct molecules from those steroidal agents

Fig. 2

Binding mode of mineralocorticoid receptor blockers to mineralocorticoid receptors. Mineralocorticoids (A) and mineralocorticoid receptor blockers (MRBs; B and C) bind to mineralocorticoid receptors (MRs) in the cytoplasm. (A) The complexes of a mineralocorticoid and a MR form a homodimer after translocation into the nucleus. Then, the homodimer complex binds to the hormone responsive element (HRE) of the target gene, leading to DNA transcription supported by co-activators (Co-A). (B) Steroidal MRBs prevent mineralocorticoids from binding to MRs, but themselves have partial agonist activity for MRs. Therefore, steroidal MRBs could also somewhat prompt transcription of the target gene. (C) Due to the “bulky” structure, nonsteroidal MRBs alter the shape of MR when binding. This modified MR complex precludes not only mineralocorticoid binding but also the recruitment of co-activators, resulting in inhibition of MR signaling