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Research ArticleArticle

Lipid Peroxide–Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples

Chungang Gu, Richard J. Lewis, Andrew S. Wells, Per H. Svensson, Vinayak P. Hosagrahara, Eskil Johnsson and Gösta Hallström
Drug Metabolism and Disposition October 2015, 43 (10) 1441-1449; DOI: https://doi.org/10.1124/dmd.115.065136
Chungang Gu
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Richard J. Lewis
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Andrew S. Wells
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Per H. Svensson
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Vinayak P. Hosagrahara
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Eskil Johnsson
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Gösta Hallström
AstraZeneca, R&D Boston, Waltham, Massachusetts (C.G., V.P.H.); AstraZeneca, R&D Mölndal, Mölndal, Sweden (R.J.L., E.J.); AstraZeneca, R&D Charnwood, Loughborough, United Kingdom (R.J.L., A.S.W.); AstraZeneca, R&D Södertälje, Södertälje, Sweden (P.H.S); AstraZeneca, R&D Wilmington, Wilmington, Delaware (C.G.); AstraZeneca, R&D Lund, Lund, Sweden (E.J., G.H.); SP Process Development, Södertälje, Sweden (P.H.S.); and Applied Physical Chemistry, Royal Institute of Technology, Stockholm, Sweden (P.H.S.)
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Abstract

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 18O atom from molecular 18O2 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.

Footnotes

    • Received April 26, 2015.
    • Accepted July 22, 2015.
  • dx.doi.org/10.1124/dmd.115.065136.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (10)
Drug Metabolism and Disposition
Vol. 43, Issue 10
1 Oct 2015
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Research ArticleArticle

Lipid Peroxide–Mediated Oxidative Rearrangement

Chungang Gu, Richard J. Lewis, Andrew S. Wells, Per H. Svensson, Vinayak P. Hosagrahara, Eskil Johnsson and Gösta Hallström
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1441-1449; DOI: https://doi.org/10.1124/dmd.115.065136

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Research ArticleArticle

Lipid Peroxide–Mediated Oxidative Rearrangement

Chungang Gu, Richard J. Lewis, Andrew S. Wells, Per H. Svensson, Vinayak P. Hosagrahara, Eskil Johnsson and Gösta Hallström
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1441-1449; DOI: https://doi.org/10.1124/dmd.115.065136
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