Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs
| Autor: | J. M. Minguez, Carlos Sunkel, Victor L. Marcheselli, Liang Xu, Elena B. Rodriguez de Turco, Pranab K. Mukherjee, Nicolas G. Bazan, M. P. Matia, Anthony Vaccarino, Julio Alvarez-Builla, Mark L. Trudell, Dennis Paul |
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| Přispěvatelé: | Universidad de Alcalá. Departamento de Química Orgánica |
| Rok vydání: | 2007 |
| Předmět: |
Male
Ciencia Magnetic Resonance Spectroscopy Science Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Pharmacology Biochemistry Transaminase Mice chemistry.chemical_compound Pharmacokinetics Oral administration In vivo CIENCIA Drug Discovery medicine Animals Molecular Biology Chemistry organic Acetaminophen Hepatotoxicity digestive oral and skin physiology Organic Chemistry Fas ligand constitutive androstane receptor Química orgánica SCIENCE Glutathione medicine.anatomical_structure Liver chemistry Hepatocyte Toxicity Molecular Medicine Analgesic medicine.drug |
| Zdroj: | e_Buah Biblioteca Digital Universidad de Alcalá instname |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2006.07.054 |
| Popis: | 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. MDA972-03-C-010 (Defense Advanced Research Programs Agency-DARPA) Neurobiotechnology Program of Louisiana |
| Databáze: | OpenAIRE |
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