Development of Small-molecule SERCA2a Stimulators: A Novel Class of Ino-lusitropic Agents

Long-term use of modulators of myocardial function has been scaled down because of the partially detrimental effects of currently available agents. Nonetheless, inotropy and lusitropy remain unmet needs in the treatment of chronic heart failure (HF). This underlies the interest in SERCA2a stimulation, a novel approach. This short review describes the identification of SERCA2a stimulating activity in istaroxime, an inotropic compound characterised by its minimal proarrhythmic effects despite its multiple targets, and the development of its derivatives into a novel class of ino-lusitropic agents. The benefits achieved with istaroxime derivatives (versus istaroxime) consist of their selectivity for SERCA2a stimulation and pharmacokinetics suitable for chronic oral administration. Considering the role of SERCA2a depression in HF and the accompanying electrical instability, selective restoration of SERCA2a function provides an appealing approach to HF therapy. Beneficial effects of SERCA2a stimulation by istaroxime have also been recently described in non-cardiac tissues, thus suggesting even broader and unexpected indications for this new class of agents.