1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ß-HSD1 inhibitors for the treatment of diabetes

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4685-91. doi: 10.1016/j.bmcl.2013.05.102. Epub 2013 Jun 11.

Abstract

Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ß-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g.

Keywords: 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazine; 11β-HSD1 inhibitors; 11β-Hydroxysteroid dehydrogenase type 1; Diabetes.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • Animals
  • Binding Sites
  • Diabetes Mellitus / drug therapy*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Stability
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Inhibitory Concentration 50
  • Mice
  • Models, Molecular*
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiazines / chemical synthesis*
  • Thiazines / chemistry
  • Thiazines / pharmacology

Substances

  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Thiazines
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1