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 KATP 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 1,1dioxide (1h), were found to be potent openers of Kir6.2/SUR1 KATP channels and were able to suppress glucose-stimulated insulin release from rat islets in vitro (EC50 = 0.04 +/- 0.01 mu M) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED50 = 4.0 mg/ kg). Structural modifications of this series of KATP channel openers have provided compounds with promising pharmacokinetic properties indicating that brief periods of beta cell rest can be achieved.