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

Abstract

The mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily and regulates body fluid and electrolyte balance. In the last years, much effort has been put into the development of non-steroidal MR antagonists that overcome the side effects of the marketed steroid drugs, and can be used for the treatment of hypertension and heart failure, among others. Initially, MR was identified in epithelial cells, however it also plays important roles in non-epithelial tissues. In this sense, it is of interest to discover ligands that might induce different MR conformational changes, leading to specific coregulator interactions, which could confer tissue-specific effects. Different series of non-steroidal ligands with diverse central scaffolds has been described, which shows antihypertensive and cardiorenal protective effects. This review covers a description of different non-steroidal MR antagonist families, with special focus on compounds under clinical development. The analysis of the three-dimensional (3D) structures of non-steroidal MR antagonists in complex with the MR ligand-binding domain (LBD), recently reported, highlights the interactions crucial for binding. The structure-activity relationships of known ligands, together with the insights provided by the 3D structures of ligand-LBD MR complexes, could help in the development of non-steroidal MR antagonists with improved properties.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…It is rapidly absorbed, has a long elimination half-life (around 20-30 h) and a dose proportional exposure [108,109]. Quantitative whole-body autoradioluminography in rats showed that it is widely distributed to the whole body, with a similar distribution to the heart and the kidneys and with a low distribution to the central nervous system [104,110]. Serious adverse events are rare, with the most common being hyperkalemia [111].…”