title: Novel carvedilol analogues that suppress store-overload-induced Ca2+ release.
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.
authors.affiliation: Department of Chemistry, University of Calgary , Calgary, Alberta T2N 1N4, Canada.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Smith
authors.forename: Aixia
authors.initials: A
authors.lastname: Wang
authors.forename: Kannan
authors.initials: K
authors.lastname: Vembaiyan
authors.forename: Jingqun
authors.initials: J
authors.lastname: Zhang
authors.forename: Cuihong
authors.initials: C
authors.lastname: Xie
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Guogen
authors.initials: G
authors.lastname: Wu
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Back
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D011412:Propanolamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D019837:Ryanodine Receptor Calcium Release Channel; D000077261:Carvedilol