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J Med Chem. 2017 Apr 13;60(7):2629-2650. doi: 10.1021/acs.jmedchem.6b01065. Epub 2017 Jan 24.

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

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Instituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
Institute of Biomedical Technologies and Department of Physiology, Campus de Ciencias de la Salud, Facultad de Medicina, Universidad de La Laguna , 38204 Tenerife, Spain.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Department of Natural Sciences, Hostos Community College of CUNY , 475 Grand Concourse, Bronx, New York 10451, United States.
Department of Chemistry, Brooklyn College , 2900 Bedford Avenue, Brooklyn, New York 11210, United States.


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.

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