Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations of cardiac calsequestrin (CASQ2) that impair its characteristic ability of Ca2+-induced polymerization-depolymerization. However, stabilizing the CASQ2 polymer by pharmacological agents to treat CPVT has not been reported so far. Here, we tested whether small molecules can stabilize CASQ2 polymers. We synthesized 24 glycinate/alaninate/acetate α-pyranone analogs and conducted the CASQ2 depolymerization assay. Most of the molecules of this class of compounds inhibited the depolymerization of the protein upon Ca2+ chelation by ethylene glycol tetraacetic acid. Structure-activity relationship studies revealed that the compounds with the 4-fluoro-phenyl group at the C-6 position of the pyranone ring and open-chain primary amine at C-4 are the most active of the class. This is the first report of an α-pyranone class of compounds with the ability to stabilize CASQ2 polymers and opens up the possibility to target Ca2+-release disorders via modulation of CASQ2 polymerization.