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.

Luraghi, A., Ferrandi, M., Barassi, P., Arici, M., Hsu, S., Torre, E., et al. (2022). Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure. JOURNAL OF MEDICINAL CHEMISTRY, 65(10), 7324-7333 [10.1021/acs.jmedchem.2c00347].

Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure

Andrea Luraghi;Martina Arici;Eleonora Torre;Carlotta Ronchi;Alessio Romerio;Antonio Zaza
;
Marcella Rocchetti
;
Francesco Peri
2022

Abstract

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.
Articolo in rivista - Articolo scientifico
Medicinal chemistry, drug development, hearth failure, Serca 2a, steroids, istaroxime;
English
7324
7333
10
Luraghi, A., Ferrandi, M., Barassi, P., Arici, M., Hsu, S., Torre, E., et al. (2022). Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure. JOURNAL OF MEDICINAL CHEMISTRY, 65(10), 7324-7333 [10.1021/acs.jmedchem.2c00347].
Luraghi, A; Ferrandi, M; Barassi, P; Arici, M; Hsu, S; Torre, E; Ronchi, C; Romerio, A; Chang, G; Ferrari, P; Bianchi, G; Zaza, A; Rocchetti, M; Peri, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/382329
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