Third-generation Mineralocorticoid Receptor Antagonists

Abstract

The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated.

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression

“…Indeed, we show in the present study that depressed patients had higher glucose levels and lower HDL cholesterol values than healthy controls. Increased aldosterone is an established risk factor for mortality in CVD, and blocking MR has beneficial effects on many CVD endpoints, including mortality 69,70 . Several prospective studies in different populations have shown that higher cortisol values are associated with cardiovascular mortality [71][72][73] .…”

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

“…The role of MR in blood pressure regulation and K + homeostasis has been therapeutically exploited using steroid analogs with competitive inhibitory activity. This strategy is commonly used for treating primary aldosteronism and additional clinical situations where a decrease in extracellular volume is advantageous, such as essential hypertension and edema associated with congestive heart failure or cirrhosis [4]. The interest in MR antagonists has greatly increased in the past two decades.…”

“…While this activity is desirable in the context of hypertensive patients treated with loop diuretics [14], it is associated with higher mortality in patients with heart failure [15]. Therefore, there is a clear need for developing selective MR modulators that preferably have a nonsteroidal nature and may present selective beneficial actions without undesired side effects [4].…”

091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

“…Although MR inactivation in skin can be beneficial by partially counteracting GCassociated undesired effects, our findings highlight that it can also have adverse consequences in this tissue in response to stressors. Therefore, prior to the use of MR antagonists the distinct cell-type specific functions of this nuclear receptor must be taken into account (Gomez-Sanchez, 2016).…”

“…For instance, skin aging was related to up-regulation of MR since its pharmacological blockade suppressed inflammation and age-related changes in a mouse model of metabolic syndrome (Nagase et al, 2013). One caveat is that these studies cannot exclude that the compounds used act through other receptors besides MR (Gomez-Sanchez, 2016). For example, the MR antagonist spironolactone can exert certain effects independently of MR likely through RXR in colon carcinoma cells (Leung et al, 2013).…”