Structure Optimization of Natural Product Catalpol to Obtain Novel and Potent Analogs against Heart Failure

Heart failure (HF) is a major global health threat, characterized by high morbidity and mortality. Targeting cardiac hypertrophy has been identified as a potential therapy for HF, with current treatments showing limited efficacy. Our research aims to address this limitation by exploring new structural classes of therapeutic agents. Starting from the natural product catalpol, we designed a series of novel catalpol analogs to break through the structural limitations of natural analogs, improve the anti-HF efficacy and metabolic properties. Among these, compound JZ19 exhibited remarkable efficacy in both myocardial cell injury assays and in an isoproterenol-induced murine HF model, outperforming catalpol. Our findings indicate that JZ19 potently reversed cardiac function by modulating the PI3K-AKT-GSK3β pathway, a key regulator of hypertrophy and apoptosis. Moreover, JZ19 showed favorable pharmacokinetic properties and safety. Overall, our results provide direct pharmacologic evidence supporting the further development of JZ19 as novel HF therapeutics by inhibiting cardiac hypertrophy and apoptosis.