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Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure
[Image: see text] The stimulation of sarcoplasmic reticulum calcium ATPase SERCA2a emerged as a novel therapeutic strategy to efficiently improve overall cardiac function in heart failure (HF) with reduced arrhythmogenic risk. Istaroxime is a clinical-phase IIb compound with a double mechanism of ac...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9150102/ https://www.ncbi.nlm.nih.gov/pubmed/35580334 http://dx.doi.org/10.1021/acs.jmedchem.2c00347 |
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author | Luraghi, Andrea Ferrandi, Mara Barassi, Paolo Arici, Martina Hsu, Shih-Che Torre, Eleonora Ronchi, Carlotta Romerio, Alessio Chang, Gwo-Jyh Ferrari, Patrizia Bianchi, Giuseppe Zaza, Antonio Rocchetti, Marcella Peri, Francesco |
author_facet | Luraghi, Andrea Ferrandi, Mara Barassi, Paolo Arici, Martina Hsu, Shih-Che Torre, Eleonora Ronchi, Carlotta Romerio, Alessio Chang, Gwo-Jyh Ferrari, Patrizia Bianchi, Giuseppe Zaza, Antonio Rocchetti, Marcella Peri, Francesco |
author_sort | Luraghi, Andrea |
collection | PubMed |
description | [Image: see text] The stimulation of sarcoplasmic reticulum calcium ATPase SERCA2a emerged as a novel therapeutic strategy to efficiently improve overall cardiac function in heart failure (HF) with reduced arrhythmogenic risk. Istaroxime is a clinical-phase IIb compound with a double mechanism of action, Na(+)/K(+) ATPase inhibition and SERCA2a stimulation. Starting from the observation that istaroxime metabolite PST3093 does not inhibit Na(+)/K(+) ATPase while stimulates SERCA2a, we synthesized a series of bioisosteric PST3093 analogues devoid of Na(+)/K(+) ATPase inhibitory activity. Most of them retained SERCA2a stimulatory action with nanomolar potency in cardiac preparations from healthy guinea pigs and streptozotocin (STZ)-treated rats. One compound was further characterized in isolated cardiomyocytes, confirming SERCA2a stimulation and in vivo showing a safety profile and improvement of cardiac performance following acute infusion in STZ rats. We identified a new class of selective SERCA2a activators as first-in-class drug candidates for HF treatment. |
format | Online Article Text |
id | pubmed-9150102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-91501022022-05-31 Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure Luraghi, Andrea Ferrandi, Mara Barassi, Paolo Arici, Martina Hsu, Shih-Che Torre, Eleonora Ronchi, Carlotta Romerio, Alessio Chang, Gwo-Jyh Ferrari, Patrizia Bianchi, Giuseppe Zaza, Antonio Rocchetti, Marcella Peri, Francesco J Med Chem [Image: see text] The stimulation of sarcoplasmic reticulum calcium ATPase SERCA2a emerged as a novel therapeutic strategy to efficiently improve overall cardiac function in heart failure (HF) with reduced arrhythmogenic risk. Istaroxime is a clinical-phase IIb compound with a double mechanism of action, Na(+)/K(+) ATPase inhibition and SERCA2a stimulation. Starting from the observation that istaroxime metabolite PST3093 does not inhibit Na(+)/K(+) ATPase while stimulates SERCA2a, we synthesized a series of bioisosteric PST3093 analogues devoid of Na(+)/K(+) ATPase inhibitory activity. Most of them retained SERCA2a stimulatory action with nanomolar potency in cardiac preparations from healthy guinea pigs and streptozotocin (STZ)-treated rats. One compound was further characterized in isolated cardiomyocytes, confirming SERCA2a stimulation and in vivo showing a safety profile and improvement of cardiac performance following acute infusion in STZ rats. We identified a new class of selective SERCA2a activators as first-in-class drug candidates for HF treatment. American Chemical Society 2022-05-17 2022-05-26 /pmc/articles/PMC9150102/ /pubmed/35580334 http://dx.doi.org/10.1021/acs.jmedchem.2c00347 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Luraghi, Andrea Ferrandi, Mara Barassi, Paolo Arici, Martina Hsu, Shih-Che Torre, Eleonora Ronchi, Carlotta Romerio, Alessio Chang, Gwo-Jyh Ferrari, Patrizia Bianchi, Giuseppe Zaza, Antonio Rocchetti, Marcella Peri, Francesco Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure |
title | Highly Selective
SERCA2a Activators: Preclinical Development
of a Congeneric Group of First-in-Class Drug Leads against Heart Failure |
title_full | Highly Selective
SERCA2a Activators: Preclinical Development
of a Congeneric Group of First-in-Class Drug Leads against Heart Failure |
title_fullStr | Highly Selective
SERCA2a Activators: Preclinical Development
of a Congeneric Group of First-in-Class Drug Leads against Heart Failure |
title_full_unstemmed | Highly Selective
SERCA2a Activators: Preclinical Development
of a Congeneric Group of First-in-Class Drug Leads against Heart Failure |
title_short | Highly Selective
SERCA2a Activators: Preclinical Development
of a Congeneric Group of First-in-Class Drug Leads against Heart Failure |
title_sort | highly selective
serca2a activators: preclinical development
of a congeneric group of first-in-class drug leads against heart failure |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9150102/ https://www.ncbi.nlm.nih.gov/pubmed/35580334 http://dx.doi.org/10.1021/acs.jmedchem.2c00347 |
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