title: Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs.
abstract: A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP. Compound 5a displayed an analgesic efficacy comparable to that of APAP. A relatively high acute oral dose of 5a (6 mmol/kg) produced no measurable toxicity, whereas the equimolar dose of APAP increased transaminase activity, depleted hepatic and renal glutathione, and resulted in mortality. In human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells, APAP, but not 5a, was associated with apoptotic cell death, Fas-ligand up-regulation, and CAR (constitutive androstane receptor) activation, contributing to a favorable safety profile of 5a as an orally delivered analgesic.
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Vaccarino
authors.forename: Dennis
authors.initials: D
authors.lastname: Paul
authors.forename: Pranab K
authors.initials: PK
authors.lastname: Mukherjee
authors.forename: Elena B
authors.initials: EB
authors.lastname: Rodríguez de Turco
authors.forename: Victor L
authors.initials: VL
authors.lastname: Marcheselli
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Mark L
authors.initials: ML
authors.lastname: Trudell
authors.forename: J M
authors.initials: JM
authors.lastname: Minguez
authors.forename: M P
authors.initials: MP
authors.lastname: Matía
authors.forename: Carlos
authors.initials: C
authors.lastname: Sunkel
authors.forename: Julio
authors.initials: J
authors.lastname: Alvarez-Builla
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D004353:Drug Evaluation, Preclinical; D008099:Liver / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice
chemical_list: D000082:Acetaminophen