New 3-alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-dioxide derivatives activate ATP-sensitive potassium channels of pancreatic beta cells
| Autor: | Thora B. Bodvarsdottir, Lars Ynddal, Søren Ebdrup, Flemming Elmelund Nielsen, Anette Frost Jensen, Carsten Enggaard Stidsen, J. Bondo Hansen, Tinna Fremming, Anne Worsaae, Hanne T. Kornø, Per Arkhammar, Harrie C. M. Boonen, Philip Wahl |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_treatment Muscle Relaxation Convergent synthesis Biological Availability In Vitro Techniques Crystallography X-Ray Chemical synthesis Cell Line Membrane Potentials Rats Sprague-Dawley Islets of Langerhans Radioligand Assay Structure-Activity Relationship In vivo Drug Discovery medicine Structure–activity relationship Animals Humans Insulin Potassium Channels Inwardly Rectifying Rats Wistar Molecular Structure Thiadiazines Chemistry Muscle Smooth Bridged Bicyclo Compounds Heterocyclic In vitro Potassium channel Cyclic S-Oxides Rats Rats Zucker Biochemistry Molecular Medicine Female Beta cell Ion Channel Gating |
| Zdroj: | Journal of medicinal chemistry. 49(14) |
| ISSN: | 0022-2623 |
| Popis: | 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 (EC(50) = 0.04 +/- 0.01 muM) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED(50) = 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. |
| Databáze: | OpenAIRE |
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