Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function

Author:

Arici Martina,Ferrandi Mara,Barassi Paolo,Hsu Shih-Che,Torre Eleonora,Luraghi Andrea,Ronchi Carlotta,Chang Gwo-Jyh,Peri Francesco,Ferrari Patrizia,Bianchi Giuseppe,Rocchetti Marcella,Zaza Antonio

Abstract

AbstractBackgroundHeart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. Istaroxime is a promising agent, which combines Na+/K+ pump inhibition with SERCA2a stimulation; however, it has a very short half-life and extensive metabolism to a molecule, named PST3093. The present work aims to investigate whether PST3093, still retains the pharmacodynamic properties of its parent compound.Methods and ResultsWe studied PST3093 for its effects on SERCA2a and Na+/K+ ATPase activities, Ca2+ dynamics in isolated myocytes and hemodynamic effects in an in-vivo rat model of diabetic (streptozotocin (STZ)-induced) cardiomyopathy. In cardiac microsomes, PST3093 did not inhibit the Na+/K+ ATPase activity, but retained SERCA2a stimulatory activity. In in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance (e.g. stroke volume) without decreasing heart rate, and reversed most STZ-induced abnormalities. Modulation of both systolic and diastolic indexes contributed to the improvement. For i.v. administration, PST3093 toxicity was considerably lower than that of istaroxime and its evaluation against 50 targets commonly involved in cardiac and extracardiac side-effects, failed to reveal significant interactions. Istaroxime infusion in patients led to accumulation of PST3093 in the plasma; clearance was substantially slower for PST3093 than for the parent compound.ConclusionsPST3093 is a “selective” SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF, particularly with prevailing diastolic dysfunction. Its pharmacodynamics are peculiar and its pharmacokinetics are suitable to prolong the cardiac beneficial effect of istaroxime infusion.Chemical compounds studied in this article: istaroxime (PubChem CID: 9841834); digoxin (PubChem CID: 2724385).

Publisher

Cold Spring Harbor Laboratory

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