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Synthesis of Benzofuran, Benzothiophene, and Benzothiazole‐Based Thioamides and their Evaluation as KATP Channel Openers
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AbstractSeveral series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel KATP 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 KATP channels using [3H]P1075 as radioligand. Selected compounds were also tested as agonists in intact cells using DiBAC4(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.
Title: Synthesis of Benzofuran, Benzothiophene, and Benzothiazole‐Based Thioamides and their Evaluation as KATP Channel Openers
Description:
AbstractSeveral series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel KATP 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 KATP channels using [3H]P1075 as radioligand.
Selected compounds were also tested as agonists in intact cells using DiBAC4(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.
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