Novel Carvedilol AnaloguesThat Suppress Store-Overload-InducedCa2䗩幪.

Carvedilolis a uniquely effective drug for the treatment of cardiacarrhythmias in patients with heart failure. This activity is in partbecause of its ability to inhibit store-overload-induced calcium release(SOICR) through the RyR2 channel. We describe the synthesis, characterization,and bioassay of ca. 100 compounds based on the carvedilol motif toidentify features that correlate with and optimize SOICR inhibition.A single-cell bioassay was employed on the basis of the RyR2-R4496Cmutant HEK-293 cell line in which calcium release from the endoplasmicreticulum through the defective channel was measured. IC50values for SOICR inhibition were thus obtained. The compounds investigatedcontained modifications to the three principal subunits of carvedilol,including the carbazole and catechol moieties, as well as the linkerchain containing the β-amino alcohol functionality. The SARresults indicate that significant alterations are tolerated in eachof the three subunits. [ABSTRACT FROM AUTHOR]