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Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples
AstraZeneca, USA.
AstraZeneca, Sweden; AstraZeneca, UK.
AstraZeneca, UK.
RISE, SP – Sveriges Tekniska Forskningsinstitut, SP Process Development, Analys och fastfas. AstraZeneca, Sweden; KTH Royal Institute of Technology, Sweden.ORCID iD: 0000-0003-2410-7366
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2015 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 43, no 10, p. 1441-1449Article in journal (Refereed) Published
Abstract [en]

This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an (18)O atom from molecular (18)O2 to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or l-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.

Place, publisher, year, edition, pages
2015. Vol. 43, no 10, p. 1441-1449
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Natural Sciences
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URN: urn:nbn:se:ri:diva-13635DOI: 10.1124/dmd.115.065136PubMedID: 26203069Scopus ID: 2-s2.0-84946205046OAI: oai:DiVA.org:ri-13635DiVA, id: diva2:1033916
Available from: 2016-10-10 Created: 2016-10-10 Last updated: 2023-06-05Bibliographically approved

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