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Research ArticleArticle

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Deepak Dalvie, Hao Sun, Cathie Xiang, Qiyue Hu, Ying Jiang and Ping Kang
Drug Metabolism and Disposition August 2012, 40 (8) 1575-1587; DOI: https://doi.org/10.1124/dmd.112.045823
Deepak Dalvie
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Hao Sun
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Cathie Xiang
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Qiyue Hu
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Ying Jiang
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Ping Kang
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Abstract

Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, π-π stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (ELUMO)], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642–4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and ELUMO). Overall, the structure-metabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structure-metabolism relationships of other AO substrates.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045823.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AO
    aldehyde oxidase
    LUMO
    lowest unoccupied molecular orbitals
    ELUMO
    energy of lowest unoccupied molecular orbitals
    DMSO
    dimethyl sulfoxide
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    ESP
    electrostatic potential
    ΔG
    energy for the formation of tetrahedral intermediate in the oxygenation of substrate
    MoCo
    molybdenum pyranopterin cofactor moiety
    XDH
    xanthine dehydrogenase
    au
    atomic units.

  • Received March 22, 2012.
  • Accepted May 15, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (8)
Drug Metabolism and Disposition
Vol. 40, Issue 8
1 Aug 2012
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Research ArticleArticle

STRUCTURE-METABOLISM RELATIONSHIP OF ZONIPORIDE

Deepak Dalvie, Hao Sun, Cathie Xiang, Qiyue Hu, Ying Jiang and Ping Kang
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1575-1587; DOI: https://doi.org/10.1124/dmd.112.045823

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Research ArticleArticle

STRUCTURE-METABOLISM RELATIONSHIP OF ZONIPORIDE

Deepak Dalvie, Hao Sun, Cathie Xiang, Qiyue Hu, Ying Jiang and Ping Kang
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1575-1587; DOI: https://doi.org/10.1124/dmd.112.045823
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