Synthesis, ultra-short acting hypnotic activity, and metabolic profile of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a] [1,3]diazepin-3-carboxylate (HIE-124)

Arch Pharm (Weinheim). 2008 Feb;341(2):81-9. doi: 10.1002/ardp.200700132.

Abstract

The synthesis and biological evaluation of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 4), as a member of a new generation of ultra-short acting hypnotics is described. HIE-124 4 exhibited potent in-vivo activity with a very rapid onset of action and a shorter duration of action with no acute tolerance or noticeable side effects than thiopental sodium. The rat in-vivo and in-vitro metabolic profile of 4 is also described. Urine was pooled from a number of animals and analyzed using electrospray liquid chromatography mass spectrometry (ESI LC-MS). HIE-124 4 was incubated with rat-liver microsomal and rat-liver hepatocyte preparations then similarly analyzed. The only metabolic product of both in-vitro and in-vivo experiments is the carboxylic acid derivative 5. HIE-124 4 has the potential use not only as a pre-anesthetic medication and as anesthesia inducer but also has the potential to be used with thiopental sodium to maintain anesthesia for longer duration.

MeSH terms

  • Animals
  • Azepines / chemical synthesis*
  • Azepines / metabolism
  • Azepines / pharmacology*
  • Carboxylic Acids / chemical synthesis*
  • Carboxylic Acids / metabolism
  • Carboxylic Acids / pharmacology*
  • Chromatography, Liquid
  • Dose-Response Relationship, Drug
  • Female
  • Hepatocytes / metabolism
  • Hypnotics and Sedatives / chemical synthesis*
  • Hypnotics and Sedatives / metabolism
  • Hypnotics and Sedatives / pharmacology*
  • In Vitro Techniques
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / metabolism
  • Thiazoles / pharmacology*

Substances

  • 8-oxo-5,6,7,8-tetrahydro-thiazolo(3,2-a)(1,3)diazepin-3-carboxylate
  • Azepines
  • Carboxylic Acids
  • Hypnotics and Sedatives
  • Thiazoles