title: 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).
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.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Kadi
authors.forename: Hassan A
authors.initials: HA
authors.lastname: El-Kashef
authors.forename: Alaa A-M
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Hassan
authors.forename: Justice
authors.initials: J
authors.lastname: Tettey
authors.forename: Mary H
authors.initials: MH
authors.lastname: Grant
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Hussein I
authors.initials: HI
authors.lastname: El-Subbagh
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C526399:8-oxo-5,6,7,8-tetrahydro-thiazolo(3,2-a)(1,3)diazepin-3-carboxylate; D001381:Azepines; D002264:Carboxylic Acids; D006993:Hypnotics and Sedatives; D013844:Thiazoles