The long-lasting istaroxime metabolite PST3093 stimulates SERCA2a and reverses disease-induced changes in cardiac function

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. 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. The results converge to identify PST3093 as a “selective” (i.e. devoid of Na+/K+ pump inhibition) SERCA2a activator and in in-vivo echocardiographic assessment, PST3093 improved overall cardiac performance, reverting many of STZ-induced abnormalities. 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. 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.