Synthesis of benzofuran, benzothiophene, and benzothiazole-based thioamides and their evaluation as K(ATP) channel openers.
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.
Fischer
Andreas
A
Institute of Organic & Macromolecular Chemistry, University of Düsseldorf, Universiätsstr. 1, Düsseldorf, Germany.
Schmidt
Claas
C
Lachenicht
Stefan
S
Grittner
Dagmar
D
Winkler
Marcus
M
Wrobel
Thomas
T
Rood
Achim
A
Lemoine
Horst
H
Frank
Walter
W
Braun
Manfred
M
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
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