RT info:eu-repo/semantics/article
T1 Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs
A1 Vaccarino, Anthony L.
A1 Paul, Dennis
A1 Mukherjee, Pranab K.
A1 Rodríguez de Turco, Elena B.
A1 Marcheselli, Victor L.
A1 Xu, Liang
A1 Trudell, Mark L.
A1 Minguez Ortega, José Miguel
A1 Matía Martín, María de la Paz
A1 Sunkel Letelier, Carlos
A1 Álvarez-Builla Gómez, Julio
A1 Bazan, Nicolas G.
K1 Acetaminophen
K1 Hepatotoxicity
K1 Analgesic
K1 Glutathione
K1 Fas ligand constitutive androstane receptor
K1 Ciencia
K1 Química orgánica
K1 Science
K1 Chemistry, organic
AB 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.
PB Elsevier
SN 0968-0896
YR 2007
FD 2007
LK http://hdl.handle.net/10017/4194
UL http://hdl.handle.net/10017/4194
LA eng
NO MDA972-03-C-010 (Defense Advanced Research Programs Agency-DARPA)
DS MINDS@UW
RD 25-abr-2024