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

Autor: Pérez-Gordillo, Felipe L., Pérez de Vega, M. Jesús, Gerona-Navarro, G., Rodríguez, Y., Alvarez de la Rosa, Diego, González-Muñiz, Rosario, Martín-Martínez, Mercedes
Přispěvatelé: Ministerio de Economía y Competitividad (España)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Aldosterone-Mineralocorticoid Receptor-Cell Biology to Translational Medicine
Digital.CSIC. Repositorio Institucional del CSIC
instname
Popis: 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.
This publication is based upon work from the EU COST Action ADMIRE BM1301 in Aldosterone and Mineralocorticoid Receptor (MR) Physiology and Pathophysiology (www.admirecosteu.com). Also supported by grants from Ministerio de Economia y Competitividad (MINECO, Spain; grant SAF2015-66275- C2-2-R and BFU2016-78374-R), CUNY (CCRG-1532), and the Hostos Office of Academic Affairs, US National Institute of Health (NIGMS) SC2GM111231
Databáze: OpenAIRE
načítá se...