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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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