title: Synthesis of benzofuran, benzothiophene, and benzothiazole-based thioamides and their evaluation as K(ATP) channel openers.
abstract: Several series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel K(ATP) channel openers in artificial cell systems: CHO cells transfected with SUR1/Kir6.2, and HEK 293 cells transfected with SUR2B/Kir6.1; these served as model systems for insulin-secreting pancreatic β cells and smooth muscle cells, respectively. All compounds were investigated with respect to their binding affinity for the SUR2B-type K(ATP) channels using [(3)H]P1075 as radioligand. Selected compounds were also tested as agonists in intact cells using DiBAC(4)(3) and DyeB (R7260) as membrane potential dyes. Remarkable affinity for SUR2B/Kir6.1 channels in the single-digit micromolar range was observed. In addition, benzothiazole-derived thioamides with sterically demanding, lipophilic substituents showed >100-fold selectivity in favor of SUR2B/Kir6.1. A one-carbon spacer between the heterocyclic skeleton and the thioamide moiety was observed to be crucial for affinity and selectivity. Two of the most potent and selective compounds were studied by crystal structure analyses.
authors.affiliation: Institute of Organic & Macromolecular Chemistry, University of Düsseldorf, Universiätsstr. 1, Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fischer
authors.forename: Claas
authors.initials: C
authors.lastname: Schmidt
authors.forename: Stefan
authors.initials: S
authors.lastname: Lachenicht
authors.forename: Dagmar
authors.initials: D
authors.lastname: Grittner
authors.forename: Marcus
authors.initials: M
authors.lastname: Winkler
authors.forename: Thomas
authors.initials: T
authors.lastname: Wrobel
authors.forename: Achim
authors.initials: A
authors.lastname: Rood
authors.forename: Horst
authors.initials: H
authors.lastname: Lemoine
authors.forename: Walter
authors.initials: W
authors.lastname: Frank
authors.forename: Manfred
authors.initials: M
authors.lastname: Braun
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry*; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D054086:KATP Channels; D008968:Molecular Conformation; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry*; D000099161:Kcnj11 Channel
chemical_list: D001572:Benzofurans; D052160:Benzothiazoles; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D013854:Thioamides; D013876:Thiophenes; D000099161:Kcnj11 Channel; C092520:uK-ATP-1 potassium channel; C088015:benzothiophene; C005465:benzothiazole; C105430:benzofuran