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Lipid Peroxide-Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples
AstraZeneca, R&D Boston, Waltham, MA USA.;AstraZeneca, R&D Wilmington, Wilmington, DE USA..
AstraZeneca, R&D Molndal, Molndal, Sweden.;AstraZeneca, R&D Charnwood, Loughborough, Leics, England..
AstraZeneca, R&D Charnwood, Loughborough, Leics, England..
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Applied Physical Chemistry. AstraZeneca, R&D Sodertalje, Sodertalje, Sweden.
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2015 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 43, no 10, 1441-1449 p.Article 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 O-18 atom from molecular O-18(2) 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, 1441-1449 p.
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Pharmacology and Toxicology
URN: urn:nbn:se:kth:diva-173757DOI: 10.1124/dmd.115.065136ISI: 000360157000004PubMedID: 26203069ScopusID: 2-s2.0-84946205046OAI: diva2:856006

QC 20150923

Available from: 2015-09-23 Created: 2015-09-18 Last updated: 2015-09-23Bibliographically approved

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