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Research ArticleArticle

Liquid Chromatography-Mass Spectrometry and Liquid Chromatography-NMR Characterization of in Vitro Metabolites of a Potent and Irreversible Peptidomimetic Inhibitor of Rhinovirus 3C Protease

Kanyin E. Zhang, Brian Hee, Caroline A. Lee, Baihong Liang and Barbara C. M. Potts
Drug Metabolism and Disposition May 2001, 29 (5) 729-734;
Kanyin E. Zhang
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Brian Hee
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Caroline A. Lee
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Baihong Liang
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Barbara C. M. Potts
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Abstract

In vitro metabolism of AG7088 [trans-(4S,2′R,5′S,3‴S)-4-{2′-4-(4-fluorobenzyl)-6′-methyl-5′-[(5"-methylisoxazole-3"-carbonylamino]-4-oxoheptanoylamino}-5-(2‴-oxopyrrolidin-3-‴-yl)pent-2-enoic acid ethyl ester] was studied in liver microsomes isolated from mice, rats, rabbits, dogs, monkeys, and humans. The structures of the metabolites were characterized by liquid chromatography (LC)-tandem mass spectrometry and LC-NMR methods. Hydrolysis of the ethyl ester to produce metabolite M4 (AG7185) is the predominant pathway in all species, with the greatest activity observed in rodents and rabbits, followed by monkeys, dogs, and humans. Several hydroxylation products were identified as minor metabolites, including diastereomers M1 and M2, with a hydroxy group at the P1-lactam moiety, and M3, with a hydroxy group at the methyl position of the methylisoxazole ring. Rodent and rabbit liver microsomes formed almost exclusively the acid metabolite M4 (AG7185), with very little hydroxylated metabolites, whereas monkey liver microsomes formed more secondary metabolites (i.e., acid analogs of the hydroxylated metabolites). The overall metabolic profile of AG7088 formed in dog liver microsomes closely resembled that of human liver microsomes; therefore, this species may be the most appropriate animal model relative to humans for exposure to AG7088 and its metabolites.

Footnotes

  • Send reprint requests to: Barbara C. M. Potts, Nereus Pharmaceuticals, Inc., 9393 Towne Centre Dr., Suite 210, San Diego, CA 92121. E-mail: bpotts{at}nereuspharm.com

  • ↵1 Current address: Merck Research Laboratories—San Diego, 505 Coast Blvd. South, La Jolla, CA 92037.

  • ↵2 Current address: Nereus Pharmaceuticals, Inc., 9393 Towne Centre Drive, Suite 210, San Diego, CA 92121.

  • Abbreviations used are::
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    LC-NMR
    liquid chromatography-NMR spectroscopy
    HPLC
    high-performance liquid chromatography
    TFA
    trifluoroacetic acid
    • Received November 16, 2000.
    • Accepted January 16, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (5)
Drug Metabolism and Disposition
Vol. 29, Issue 5
1 May 2001
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Research ArticleArticle

Liquid Chromatography-Mass Spectrometry and Liquid Chromatography-NMR Characterization of in Vitro Metabolites of a Potent and Irreversible Peptidomimetic Inhibitor of Rhinovirus 3C Protease

Kanyin E. Zhang, Brian Hee, Caroline A. Lee, Baihong Liang and Barbara C. M. Potts
Drug Metabolism and Disposition May 1, 2001, 29 (5) 729-734;

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Research ArticleArticle

Liquid Chromatography-Mass Spectrometry and Liquid Chromatography-NMR Characterization of in Vitro Metabolites of a Potent and Irreversible Peptidomimetic Inhibitor of Rhinovirus 3C Protease

Kanyin E. Zhang, Brian Hee, Caroline A. Lee, Baihong Liang and Barbara C. M. Potts
Drug Metabolism and Disposition May 1, 2001, 29 (5) 729-734;
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