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Research ArticleArticle

Elucidating the Mechanism of Cytochrome P450–Mediated Pyrimidine Ring Conversion to Pyrazole Metabolites with the BACE1 Inhibitor GNE-892 in Rats

Ryan Takahashi, Shuguang Ma, Alan Deese, Qin Yue, Heasook Kim-Kang, Yijun Yi, Michael Siu, Kevin W. Hunt, Nicholas C. Kallan, Cornelis E.C.A. Hop, Xingrong Liu and S. Cyrus Khojasteh
Drug Metabolism and Disposition May 2014, 42 (5) 890-898; DOI: https://doi.org/10.1124/dmd.114.057141
Ryan Takahashi
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Shuguang Ma
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Alan Deese
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Qin Yue
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Heasook Kim-Kang
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Yijun Yi
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Michael Siu
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Kevin W. Hunt
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Nicholas C. Kallan
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Cornelis E.C.A. Hop
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Xingrong Liu
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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S. Cyrus Khojasteh
Departments of Drug Metabolism and Pharmacokinetics (R.T., S.M., Q.Y.,1 C.E.H., X.L., S.C.K), Small Molecule Pharmaceutical Sciences (A.D.), and Discovery Chemistry (M.S.), Genentech, Inc., South San Francisco, California; XenoBiotic Laboratories, Inc., Plainsboro, New Jersey (H.K., Y.Y.); and Array BioPharma, Boulder, Colorado (K.W.H., N.C.K.)
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Abstract

We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3′,3′-trimethyl-7′-(pyrimidin-5-yl)-3′,4′-dihydro-2′H-spiro[imidazole-4,1′-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the 14C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.

Footnotes

    • Received January 16, 2014.
    • Accepted March 4, 2014.
  • ↵1 Current affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.

  • Parts of this work were previously presented at The 18th North American Meeting of the International Society for the Study of Xenobiotics, 2012 Oct 14–18; Dallas, TX.

  • The authors were employees of Genentech, XenoBiotic Laboratories, or Array BioPharma at the time this work was completed.

  • dx.doi.org/10.1124/dmd.114.057141.

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (5)
Drug Metabolism and Disposition
Vol. 42, Issue 5
1 May 2014
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Research ArticleArticle

Metabolic Conversion of Pyrimidine to Pyrazole by P450

Ryan Takahashi, Shuguang Ma, Alan Deese, Qin Yue, Heasook Kim-Kang, Yijun Yi, Michael Siu, Kevin W. Hunt, Nicholas C. Kallan, Cornelis E.C.A. Hop, Xingrong Liu and S. Cyrus Khojasteh
Drug Metabolism and Disposition May 1, 2014, 42 (5) 890-898; DOI: https://doi.org/10.1124/dmd.114.057141

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Research ArticleArticle

Metabolic Conversion of Pyrimidine to Pyrazole by P450

Ryan Takahashi, Shuguang Ma, Alan Deese, Qin Yue, Heasook Kim-Kang, Yijun Yi, Michael Siu, Kevin W. Hunt, Nicholas C. Kallan, Cornelis E.C.A. Hop, Xingrong Liu and S. Cyrus Khojasteh
Drug Metabolism and Disposition May 1, 2014, 42 (5) 890-898; DOI: https://doi.org/10.1124/dmd.114.057141
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