Istaroxime Metabolite PST3093 Selectively Stimulates SERCA2a and Reverses Disease-Induced Changes in Cardiac Function

Abstract

Heart 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. We studied PST3093 for its effects on SERCA2a and Na⁺/K⁺ ATPase activities, Ca²⁺ dynamics in isolated myocytes and hemodynamic effects in an <i>in-vivo</i> rat model of diabetic (streptozotocin (STZ)-induced) cardiomyopathy. Istaroxime 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 <i>in-vivo</i> 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. Overall, 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. <b>Significance Statement</b> Heart failure (HF) treatment would benefit from the availability of ino-lusitropic agents with a favourable profile. PST3093 is the main metabolite of istaroxime, a promising agent combining Na⁺/K⁺ pump inhibition and SERCA2a stimulation. PST3093 shows a longer half-life in human circulation compared to parent drug, activates SERCA2a, doesn’t inhibit Na⁺/K⁺ pump and improves cardiac performance in a model of diabetic cardiomyopathy. Overall, PST3093 as selective SERCA2a activator can be considered the prototype of a novel pharmacodynamic category for HF treatment.

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