Modulating Mineralocorticoid Receptor with Non-steroidal Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-Target Side Effects

• Published in: Journal of medicinal chemistry 2017-04, Vol.60 (7), p.2629-2650
• Main Authors: Martín-Martínez, Mercedes, Pérez-Gordillo, Felipe L, Álvarez de la Rosa, Diego, Rodríguez, Yoel, Gerona-Navarro, Guillermo, González-Muñiz, Rosario, Zhou, Ming-Ming
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Benzoxazines - chemistry; Benzoxazines - pharmacology; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Drug Discovery; Humans; Ligands; Macrolides - chemistry; Macrolides - pharmacology; Mineralocorticoid Receptor Antagonists - chemistry; Mineralocorticoid Receptor Antagonists - pharmacology; Models, Molecular; Oxazolidinones - chemistry; Oxazolidinones - pharmacology; Peptides - chemistry; Peptides - pharmacology; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, Mineralocorticoid - chemistry; Receptors, Mineralocorticoid - metabolism; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01065

Steroidal mineralo­corticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but they present challenging issues of complex chemical synthesis, undesirable physical properties, and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain of the MR and recruit different co-regulators to produce tissue-specific therapeutic effects. Several academic groups and pharmaceutical companies have been developing a series of non-steroidal ligands that consist of different chemical scaffolds, yielding MR antagonists currently evaluated in clinical studies for the treatment of congestive heart failure, hypertension, or diabetic nephropathy. The main focus of this Perspective is to review the reported structure–activity relationships of the different series of compounds, as well as the structural studies that contribute to a better understanding of the receptor active site and are also helpful for optimization processes.