Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists

Autor: Felipe Luis Pérez-Gordillo, Natalia Serrano-Morillas, Luz Marina Acosta-García, María Teresa Aranda, Daniela Passeri, Roberto Pellicciari, María Jesús Pérez de Vega, Rosario González-Muñiz, Diego Alvarez de la Rosa, Mercedes Martín-Martínez
Přispěvatelé: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España)
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: International Journal of Molecular Sciences
Volume 24
Issue 3
Pages: 2439
ISSN: 1422-0067
DOI: 10.3390/ijms24032439
Popis: The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators.
This research was funded by grants BFU2016-78374-R and PID2019-105339RB-I00 to D.A.d.l.R., funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe”. RTI-2018-097189-B-C22, PID2021-126423OB-C22 and CSIC (202180E073) to MMM. N.S.-M. was supported by fellowship BES-2014-068280, funded by MCIN/AEI/10.13039/501100011033 and “ESF Investing in your future”.
Databáze: OpenAIRE
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