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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 May 17

PMID 35580334

Authors

Andrea Luraghi

Mara Ferrandi

Paolo Barassi

Martina Arici

Shih-Che Hsu

Eleonora Torre

Carlotta Ronchi

Alessio Romerio

Gwo-Jyh Chang

Patrizia Ferrari

Giuseppe Bianchi

Antonio Zaza

Marcella Rocchetti

Francesco Peri

Affiliations

Soon will be listed here.

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.

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