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Rapid CommunicationShort Communication

Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450–Mediated Fused Ring Metabolites of GDC-0623, a MAPK/ERK Kinase Inhibitor

Ryan H. Takahashi, Shuguang Ma, Sarah J. Robinson, Qin Yue, Edna F. Choo and S. Cyrus Khojasteh
Drug Metabolism and Disposition December 2015, 43 (12) 1929-1933; DOI: https://doi.org/10.1124/dmd.115.067181
Ryan H. Takahashi
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., S.M., Q.Y., E.F.C., S.C.K.) and Small Molecule Pharmaceutical Sciences (S.J.R.), Genentech, Inc., South San Francisco, California
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Shuguang Ma
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., S.M., Q.Y., E.F.C., S.C.K.) and Small Molecule Pharmaceutical Sciences (S.J.R.), Genentech, Inc., South San Francisco, California
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Sarah J. Robinson
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., S.M., Q.Y., E.F.C., S.C.K.) and Small Molecule Pharmaceutical Sciences (S.J.R.), Genentech, Inc., South San Francisco, California
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Qin Yue
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., S.M., Q.Y., E.F.C., S.C.K.) and Small Molecule Pharmaceutical Sciences (S.J.R.), Genentech, Inc., South San Francisco, California
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Edna F. Choo
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., S.M., Q.Y., E.F.C., S.C.K.) and Small Molecule Pharmaceutical Sciences (S.J.R.), Genentech, Inc., South San Francisco, California
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S. Cyrus Khojasteh
Departments of Drug Metabolism and Pharmacokinetics (R.H.T., S.M., Q.Y., E.F.C., S.C.K.) and Small Molecule Pharmaceutical Sciences (S.J.R.), Genentech, Inc., South San Francisco, California
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Abstract

Two isomeric metabolites of GDC-0623 [5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide], a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase inhibitor, were identified in radiolabeled mass balance studies in rats and dogs (approximately 5% in excreta) and were also observed in human circulation (nonradiolabeled). Mass spectrometric data indicated that both metabolites had formed a new ring structure fused to the imidazopyridine core. Given their unusual structures, we conducted experiments to elucidate their chemical structures and understand the mechanisms for their formation. For the first metabolite, M14, a pyrazol-3-ol ring was generated by N-N bond formation between the aniline and hydroxamate. For the second metabolite, M13, an imidazol-2-one was generated by a Hofmann-type rearrangement that involved C-C bond cleavage and C-N bond formation. Both reactions were catalyzed by CYP2C9 and CYP2C19. M14 was generated directly from GDC-0623 and we speculate that its formation was via oxidative activation of the hydroxamic ester by cytochrome P450 (P450) and intramolecular nucleophilic displacement of the ester side chain. M13 (the rearranged metabolite) formed from the N-reduced hydroxamate (amide) and not from GDC-0623 directly. We propose for M13 that a P450-mediated reaction formed a cationic amide intermediate, which enabled the molecular rearrangement of the imidazopyridine core migrating from the amide carbon to the nitrogen and subsequent cyclization reaction. Each of these metabolic pathways constitutes a novel biotransformation mediated by P450 enzymes.

Footnotes

    • Received September 14, 2015.
    • Accepted October 2, 2015.
  • ↵1 Current affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.

  • dx.doi.org/10.1124/dmd.115.067181.

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

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Rapid CommunicationShort Communication

Unusual Biotransformations of GDC-0623 by P450

Ryan H. Takahashi, Shuguang Ma, Sarah J. Robinson, Qin Yue, Edna F. Choo and S. Cyrus Khojasteh
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1929-1933; DOI: https://doi.org/10.1124/dmd.115.067181

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Rapid CommunicationShort Communication

Unusual Biotransformations of GDC-0623 by P450

Ryan H. Takahashi, Shuguang Ma, Sarah J. Robinson, Qin Yue, Edna F. Choo and S. Cyrus Khojasteh
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1929-1933; DOI: https://doi.org/10.1124/dmd.115.067181
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