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Research ArticleArticle

Formation of Unusual Glutamate Conjugates of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]- 4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423) and Its Analogs: The Role of γ-Glutamyltranspeptidase in the Biotransformation of Benzylamines

Abdul Mutlib, John Shockcor, Shiang-Yuan Chen, Robert Espina, Jianrong Lin, Nilsa Graciani, Shimoga Prakash and Liang-Shang Gan
Drug Metabolism and Disposition October 2001, 29 (10) 1296-1306;
Abdul Mutlib
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John Shockcor
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Shiang-Yuan Chen
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Robert Espina
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Jianrong Lin
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Nilsa Graciani
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Shimoga Prakash
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Liang-Shang Gan
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Abstract

The role of γ-glutamyltranspeptidase (GGT) in transferring glutamate from endogenous glutathione (GSH) to the benzylamine moiety of a compound, such as 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423), is described. Studies were performed with structurally related analogs of DPC 423 to demonstrate that this type of reaction was common to compounds possessing a benzylamine group. Synthesizing appropriate standards and confirming by liquid chromatography (LC)/mass spectroscopy and LC/NMR made unambiguous assignments of the structures of glutamate conjugates of DPC 423. The use of stable isotope-labeled GSH for metabolism studies has not been described before. In the present study, we report the novel use of deuterated GSH in conjunction with mass spectral analysis to demonstrate the glutamate transfer to the benzylamines in the presence of GGT. To further demonstrate that the α protons on the benzylamines and glutamate (as part of glutathione) were unaffected during the transpeptidation, these protons were replaced with deuterium. Acivicin (AT-125), a potent and selective inhibitor of GGT, was used to abolish the formation of the glutamate conjugates of DPC 423 in vitro and in vivo. This provided further evidence of the role of GGT in forming the glutamate conjugates of benzylamines. This study demonstrated conclusively that GGT was responsible for mediating the transfer of glutamic acid from GSH to the benzylamine moiety of a series of structurally related compounds.

Footnotes

  • Abbreviations used are::
    LC
    liquid chromatography
    MS
    mass spectroscopy
    MS/MS
    tandem mass spectroscopy
    GGT
    γ-glutamyltranspeptidase
    GSH
    glutathione
    Fmoc
    N-α-(fluorenyl)methoxycarbonyl
    TFA
    trifluoroacetic acid
    DMF
    dimethylformamide
    HPLC
    high-pressure liquid chromatography
    HBTU
    2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
    ESI-MS
    electrospray ionization-mass spectroscopy
    amu
    atomic mass unit
    HMBC
    heteronuclear multiple bond correlation
    • Received April 4, 2001.
    • Accepted June 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (10)
Drug Metabolism and Disposition
Vol. 29, Issue 10
1 Oct 2001
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Formation of Unusual Glutamate Conjugates of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]- 4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423) and Its Analogs: The Role of γ-Glutamyltranspeptidase in the Biotransfor…
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Research ArticleArticle

Formation of Unusual Glutamate Conjugates of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]- 4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423) and Its Analogs: The Role of γ-Glutamyltranspeptidase in the Biotransformation of Benzylamines

Abdul Mutlib, John Shockcor, Shiang-Yuan Chen, Robert Espina, Jianrong Lin, Nilsa Graciani, Shimoga Prakash and Liang-Shang Gan
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1296-1306;

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Research ArticleArticle

Formation of Unusual Glutamate Conjugates of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-biphenyl]- 4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC 423) and Its Analogs: The Role of γ-Glutamyltranspeptidase in the Biotransformation of Benzylamines

Abdul Mutlib, John Shockcor, Shiang-Yuan Chen, Robert Espina, Jianrong Lin, Nilsa Graciani, Shimoga Prakash and Liang-Shang Gan
Drug Metabolism and Disposition October 1, 2001, 29 (10) 1296-1306;
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