Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs
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 profi...
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Published in | Bioorganic & medicinal chemistry Vol. 15; no. 5; pp. 2206 - 2215 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Elsevier Ltd
01.03.2007
Elsevier Science |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2006.07.054 |