6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives potently and selectively activate ATP sensitive potassium channels of pancreatic beta-cells

J Med Chem. 2002 Sep 12;45(19):4171-87. doi: 10.1021/jm0208121.

Abstract

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [(3)H]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 K(ATP) channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K(ATP) channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.

MeSH terms

  • ATP-Binding Cassette Transporters
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Binding, Competitive
  • Biological Availability
  • Blood Pressure / drug effects
  • Body Temperature / drug effects
  • Cell Line
  • Female
  • Glucose
  • Heart Rate / drug effects
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / physiology
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Potassium Channels / agonists*
  • Potassium Channels / metabolism
  • Potassium Channels, Inwardly Rectifying
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Drug
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonylurea Receptors
  • Thiadiazines / chemical synthesis*
  • Thiadiazines / chemistry
  • Thiadiazines / pharmacology

Substances

  • ABCC8 protein, human
  • ATP-Binding Cassette Transporters
  • Abcc8 protein, mouse
  • Abcc8 protein, rat
  • Insulin
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Receptors
  • Thiadiazines
  • Adenosine Triphosphate
  • Glucose