Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 5; pp. 2206 - 2215
• Main Authors: Vaccarino, Anthony L., Paul, Dennis, Mukherjee, Pranab K., Rodríguez de Turco, Elena B., Marcheselli, Victor L., Xu, Liang, Trudell, Mark L., Minguez, J.M., Matía, M.P., Sunkel, Carlos, Alvarez-Builla, Julio, Bazan, Nicolas G.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2007; Elsevier Science
• Subjects: Acetaminophen; Acetaminophen - analogs & derivatives; Acetaminophen - chemical synthesis; Acetaminophen - pharmacology; Analgesic; Analgesics; Animals; Biological and medical sciences; Drug Evaluation, Preclinical; Fas ligand constitutive androstane receptor; Glutathione; Hepatotoxicity; Liver - drug effects; Magnetic Resonance Spectroscopy; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Neuropharmacology; Pharmacology. Drug treatments; Fas ligand constitutive androstane receptor; Analgesic; Acetaminophen; Hepatotoxicity; Glutathione; Toxicity; Liver; Cytotoxicity; Paracetamol; Hepatocyte; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Human; Sulfur nitrogen heterocycle; Acute; Chain length; Rodentia; Benzene derivatives; Oral administration; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Phenols; Carboxamide; Pharmacokinetics
• DOI: 10.1016/j.bmc.2006.07.054
• ISSN: 0968-0896

A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3 H)-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.