| Literature DB >> 24124794 |
Chris D Smith1, Aixia Wang, Kannan Vembaiyan, Jingqun Zhang, Cuihong Xie, Qiang Zhou, Guogen Wu, S R Wayne Chen, Thomas G Back.
Abstract
Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because 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 to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.Entities:
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Year: 2013 PMID： 24124794 PMCID： PMC3896386 DOI： 10.1021/jm401090a
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446