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Research ArticleArticle

Reaction of Homopiperazine with Endogenous Formaldehyde: A Carbon Hydrogen Addition Metabolite/Product Identified in Rat Urine and Blood

Scott Martin, Eva M. Lenz, Dave Temesi, Martin Wild and Malcolm R. Clench
Drug Metabolism and Disposition August 2012, 40 (8) 1478-1486; DOI: https://doi.org/10.1124/dmd.112.044917
Scott Martin
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Eva M. Lenz
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Dave Temesi
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Martin Wild
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Malcolm R. Clench
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Abstract

Drug reactivity and bioactivation are of major concern to the development of potential drug candidates in the pharmaceutical industry (Chem Res Toxicol 17:3–16, 2004; Chem Res Toxicol 19:889–893, 2006). Identifying potentially problematic compounds as soon as possible in the discovery process is of great importance, so often early in vitro screening is used to speed up attrition. Identification of reactive moieties is relatively straightforward with appropriate in vitro trapping experiments; however, on occasion unexpected reactive intermediates can be found later during more detailed in vivo studies. Here, we present one such example involving a series of compounds from an early drug discovery campaign. These compounds were found to react with endogenous formaldehyde from a rat in vivo study, resulting in the formation of novel +13-Da bridged homopiperazine products (equivalent to the addition of one carbon and one hydrogen atom), which were detected in urine and blood. The identification of these +13-Da products and their origin and mechanism of formation are described in detail through analyses of a representative homopiperazine compound [N-(3-(3-fluorophenyl)-1,2,4-thiadiazol-5-yl)-4-(4-isopropyl-1,4-diaze-pane-2-carbonyl)piperazine-1-carboxamide (AZX)] by liquid chromatography-UV-mass spectrometry, 1H NMR, and chemical tests.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.112.044917.

  • ABBREVIATIONS:

    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MS
    mass spectrometry
    AZX
    N-(3-(3-fluorophenyl)-1,2,4-thiadiazol-5-yl)-4-(4-isopropyl-1,4-diaze-pane-2-carbonyl)piperazine-1-carboxamide
    ACN
    acetonitrile
    MeOH
    methanol
    UPLC
    ultra high-performance liquid chromatography
    ESI
    electrospray ionization
    HCD
    higher energy collisional dissociation
    COSY
    correlation spectroscopy
    ROESY
    rotating frame Overhauser effect spectroscopy
    +ESI
    positive ion electrospray ionization
    RT
    retention time.

  • Received February 3, 2012.
  • Accepted May 1, 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

REACTION OF HOMOPIPERAZINE WITH FORMALDEHYDE

Scott Martin, Eva M. Lenz, Dave Temesi, Martin Wild and Malcolm R. Clench
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1478-1486; DOI: https://doi.org/10.1124/dmd.112.044917

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Research ArticleArticle

REACTION OF HOMOPIPERAZINE WITH FORMALDEHYDE

Scott Martin, Eva M. Lenz, Dave Temesi, Martin Wild and Malcolm R. Clench
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1478-1486; DOI: https://doi.org/10.1124/dmd.112.044917
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