Dataset supporting Development of activators for SERCA2a for heart failure treatments

Our primary aim in the present study is to discover drug-like small-molecule activators that improve SERCA function for the treatment of heart failure. We previously identified a promising hit compound, N-aryl-N-alkyl-thiophene-2-carboxamide (designated compound 1) using an NADH-coupled ATPase activity assay of the skeletal sarco/endoplasmic reticulum (SR) ATPase (SERCA1a) transporter for high-throughput screening (HTS) of a large compound library. At micromolar concentrations, compound 1 activated the Ca2+-ATPase activity and Ca2+-uptake function of the cardiac SERCA isoform (SERCA2a), using cardiac SR. Further, compound 1 increased SR Ca2+ load in cardiomyocytes. Here, we report on the medicinal chemistry development of compound 1, with the goal of improving its potency and efficacy on SERCA2a functional activities. Systemic modification of the three moieties of compound 1 resulted in a gallery of analogs that were functionally evaluated with Ca2+-ATPase activity and Ca2+-uptake measurements on SERCA2a in porcine cardiac SR. Correlation of the effects of the analogs’ chemical structure-activity relationship (SAR) revealed several analogs with improved potency and efficacy. Solubility, stability, and toxicity measurements of a subset of analogs were used to explore the lead-like potential of this chemical group. In this study, we demonstrate a path of using medicinal chemistry for developing drugs to treat heart failure.