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

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.

Automated summary

Stimulation of sarcoplasmic reticulum calcium ATPase SERCA2a is a promising therapeutic strategy for heart failure. Istaroxime, a compound with dual mechanisms of action, inhibits Na+/K+ ATPase and stimulates SERCA2a. By synthesizing a series of analogues, we identified a compound that lacks Na+/K+ ATPase inhibitory activity but retains SERCA2a stimulatory action. Further studies in isolated cardiomyocytes and a rat model showed that the compound is safe and improves cardiac performance, making it a potential drug candidate for heart failure treatment.