6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic β-cells

被引：47

作者：

Nielsen, FE ^{[1
]}

Bodvarsdottir, TB ^{[1
]}

Worsaae, A ^{[1
]}

MacKay, P ^{[1
]}

Stidsen, CE ^{[1
]}

Boonen, HCM ^{[1
]}

Pridal, L ^{[1
]}

Arkhammar, POG ^{[1
]}

Wahl, P ^{[1
]}

Ynddal, L ^{[1
]}

Junager, F ^{[1
]}

Dragsted, N ^{[1
]}

Tagmose, TM ^{[1
]}

Mogensen, JP ^{[1
]}

Koch, A ^{[1
]}

Treppendahl, SP ^{[1
]}

Hansen, JB ^{[1
]}

机构：

[1] Novo Nordisk AS, Res & Dev, DK-2760 Malov, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 19期

关键词：

D O I：

10.1021/jm0208121

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K-ATP) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [H-3]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 KATP channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K-ATP channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.

引用

页码：4171 / 4187

页数：17

共 71 条

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