Referenced in: none

Automatically associated channels: Kir6.2

Title: New 3-alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-dioxide derivatives activate ATP-sensitive potassium channels of pancreatic beta cells.

Authors: Flemming E Nielsen, Søren Ebdrup, Anette Frost Jensen, Lars Ynddal, Thora B Bodvarsdottir, Carsten Stidsen, Anne Worsaae, Harrie C M Boonen, Per O G Arkhammar, Tinna Fremming, Philip Wahl, Hanne T Kornø, J Bondo Hansen

Journal, date & volume: J. Med. Chem., 2006 Jul 13 , 49, 4127-39

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16821773

Abstract
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.