New 3-Alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-Dioxide Derivatives Activate ATP-Sensitive Potassium Channels of Pancreatic Beta Cells

Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K ATP channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The c...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-07, Vol.49 (14), p.4127-4139
Main Authors: Nielsen, Flemming E, Ebdrup, Søren, Jensen, Anette Frost, Ynddal, Lars, Bodvarsdottir, Thora B, Stidsen, Carsten, Worsaae, Anne, Boonen, Harrie C. M, Arkhammar, Per O. G, Fremming, Tinna, Wahl, Philip, Kornø, Hanne T, Hansen, J. Bondo
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biological Availability
Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Cell Line
Crystallography, X-Ray
Cyclic S-Oxides - chemical synthesis
Cyclic S-Oxides - chemistry
Cyclic S-Oxides - pharmacology
Female
General and cellular metabolism. Vitamins
Humans
In Vitro Techniques
Insulin - blood
Ion Channel Gating
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
Male
Medical sciences
Membrane Potentials - drug effects
Molecular Structure
Muscle Relaxation - drug effects
Muscle, Smooth - drug effects
Muscle, Smooth - physiology
Pharmacology. Drug treatments
Potassium Channels, Inwardly Rectifying - chemistry
Potassium Channels, Inwardly Rectifying - drug effects
Potassium Channels, Inwardly Rectifying - physiology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Rats, Wistar
Rats, Zucker
Structure-Activity Relationship
Thiadiazines - chemical synthesis
Thiadiazines - chemistry
Thiadiazines - pharmacology
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Summary:Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K ATP channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The crystal structure and a convergent synthesis of 1a are presented together with a range of new analogues of 1a. Several compounds, e.g., 6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1h), were found to be potent openers of Kir6.2/SUR1 K ATP channels and were able to suppress glucose-stimulated insulin release from rat islets in vitro (EC50 = 0.04 ± 0.01 μM) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED50 = 4.0 mg/kg). Structural modifications of this series of K ATP channel openers have provided compounds with promising pharmacokinetic properties indicating that brief periods of beta cell rest can be achieved.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060042j