Background and Purpose. Heart failure (HF) therapeutic toolkit would strongly benefit from the availability of ino-lusitropic agents with a favorable pharmacodynamics and safety profile. Istaroxime is an agent, combining Na+/K+ pump inhibition and SERCA2a stimulation, shown by phase 2 trials to be promising in the acute setting. As PST3093 is an istaroxime metabolite reaching plasma concentration and duration greater than those of istaroxime, its evaluation is indispensable to establish its contribution to the istaroxime clinical efficacy. Experimental Approach. We studied PST3093 for its effects on SERCA2a and Na+/K+ ATPase activities, Ca2+ dynamics in intact myocytes and hemodynamic effects in an in-vivo rat model of diabetic (streptozotocin (STZ)-induced) cardiomyopathy. Key Results. The results converge to identify PST3093 as a “selective” (i.e. devoid of Na+/K+ pump inhibition) SERCA2a activator, thus differentiating it from its parent compound istaroxime. In in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance (stroke volume and cardiac output) without decreasing heart rate, thus reversing many of 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 a panel of 50 targets commonly involved in cardiac and extracardiac side-effects, failed to reveal significant interactions. Conclusion and Implication. PST3093 is a “selective” SERCA2a activator, the prototype of a novel pharmacodynamic category with a potential in the ino-lusitropic approach to HF therapy that may contribute to the clinical efficacy of istaroxime infusion.

Background and Purpose. The sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) depression substantially contributes to diastolic dysfunction in heart failure (HF), suggesting that SERCA2a stimulation may be a “causal” HF therapy. Istaroxime is a drug endowed with both a SERCA2a stimulatory activity and a Na+/K+ pump inhibitory activity for the acute HF treatment. Its main metabolite PST3093 shows a more favorable therapeutic profile as compared to the parent drug, but it is still unsuitable for chronic usage. Novel PST3093 derivatives have been recently developed for oral (chronic) HF treatment; compound 8 was selected among them and here characterized. Experimental Approach. Effects of compound 8 were evaluated in a context of SERCA2a depression, by using streptozotocin-treated rats, a well-known model of diastolic dysfunction. The impact of SERCA2a stimulation by compound 8 was assessed both at the cellular level ad in vivo, following i.v. infusion (acute effects) or oral administration (chronic effects). Key Results. As expected from SERCA2a stimulation, compound 8 induced SR Ca2+ compartmentalization in STZ myocytes. In-vivo echocardiographic analysis during i.v. infusion and after repeated oral administration of compound 8, detected a significant improvement of diastolic function. Moreover, compound 8 did not affect electrical activity of healthy guinea-pig myocytes, in line with the absence of off-target effects. Finally, compound 8 was well tolerated in mice with no evidence of acute toxicity. Conclusion and Implications. The pharmacological evaluation of compound 8 indicates that it may be a safe and selective drug for a “causal” treatment of chronic HF by restoring SERCA2a activity.