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

Arici, M.; Ferrandi, M.; Hsu, S.-C.; Torre, E.; Barassi, P.; Luraghi, A.; Ronchi, C.; Chang, G.-J.; Peri, F.; Ferrari, P.; Bianchi, G.; Rocchetti, M.; Zaza, A.

doi:10.1101/2021.08.17.455204

bioRxiv · 10.1101/2021.08.17.455204

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

Arici, M.·Ferrandi, M.·Hsu, S.-C.·Torre, E.·Barassi, P.·Luraghi, A.·Ronchi, C.·Chang, G.-J.·Peri, F.·Ferrari, P.·Bianchi, G.·Rocchetti, M.·Zaza, A.

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Abstract

BackgroundHeart 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 and pharmacokinetic properties of its parent compound. MethodsWe 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. ResultsIstaroxime infusion in HF patients led to accumulation of PST3093 in the plasma; clearance was substantially slower for PST3093 than for istaroxime. In cardiac rat preparations PST3093 did not inhibit the Na+/K+ ATPase activity, but retained SERCA2a stimulatory activity. In in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance and reversed most STZ-induced abnormalities. PST3093 i.v. toxicity was considerably lower than that of istaroxime and it failed to significantly interact with 50 off-targets. ConclusionsOverall, PST3093 is a "selective" SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF with prevailing diastolic dysfunction. Its pharmacodynamics are peculiar and its pharmacokinetics are suitable to prolong the cardiac beneficial effect of istaroxime infusion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/455204v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@bc9220org.highwire.dtl.DTLVardef@1d7a6eorg.highwire.dtl.DTLVardef@1510c71org.highwire.dtl.DTLVardef@7f037_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Arici, M., Ferrandi, M., Hsu, S.-C., Torre, E., Barassi, P., Luraghi, A., Ronchi, C., Chang, G.-J., Peri, F., Ferrari, P., Bianchi, G., Rocchetti, M., Zaza, A.. 2021-08-17. Istaroxime metabolite PST3093 selectively stimulates SERCA2a and reverses disease-induced changes in cardiac function. https://doi.org/10.1101/2021.08.17.455204

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