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

J Med Chem. 2006 Jul 13;49(14):4127-39. doi: 10.1021/jm060042j.

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.

MeSH terms

  • Animals
  • 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
  • Humans
  • In Vitro Techniques
  • Insulin / blood
  • Ion Channel Gating
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Molecular Structure
  • Muscle Relaxation / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • 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

Substances

  • 6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno(3,2-e)-1,2,4-thiadiazine
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclic S-Oxides
  • Insulin
  • Kir6.2 channel
  • NN 414
  • Potassium Channels, Inwardly Rectifying
  • Thiadiazines