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

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.

• 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 10 Pg. 7324-7333 (05 26 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35580334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Animals
• Arrhythmias, Cardiac
• Calcium (metabolism)
• Guinea Pigs
• Heart Failure (metabolism)
• Myocytes, Cardiac (metabolism)
• Rats
• Sarcoplasmic Reticulum Calcium-Transporting ATPases