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Research ArticleArticle

Identification of 2-Aminothiazolobenzazepine Metabolites in Human, Rat, Dog, and Monkey Microsomes by Ion-Molecule Reactions in Linear Quadrupole Ion Trap Mass Spectrometry

Minli Zhang, Ryan Eismin, Hilkka Kenttämaa, Hui Xiong, Ye Wu, Doug Burdette and Rebecca Urbanek
Drug Metabolism and Disposition March 2015, 43 (3) 358-366; DOI: https://doi.org/10.1124/dmd.114.061978
Minli Zhang
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Ryan Eismin
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Hilkka Kenttämaa
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Hui Xiong
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Ye Wu
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Doug Burdette
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Rebecca Urbanek
Drug Metabolism and Pharmacokinetics (M.Z.), and Medicinal Chemistry (Y.W., R.U.), AstraZeneca Pharmaceuticals, Boston, Massachusetts; Department of Chemistry, University of Arizona, Tucson, Arizona (R.E.); Department of Chemistry, Purdue University, West Lafayette, Indiana (H.K.); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (H.X.); Novartis Institutes for BioMedical Research, Boston, Massachusetts (D.B.)
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Abstract

2-Aminothiazolobenzazepine (2-ATBA), 7-[(1-methyl-1H-pyrazol-4-yl)methyl]-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepin-2-amine, is a D2 partial agonist that has demonstrated antipsychotic effects in a rodent in vivo efficacy model. The metabolite profile showed that 2-ATBA is mainly metabolized by oxidation. However, identification of the oxidation site(s) in the 2-aminothiazole group presents a challenge for the traditional metabolite identification methods such as liquid chromatography/mass spectrometry and NMR due to the lack of unique tandem mass spectrometry fragmentation patterns for ions with the 2-aminothiazole group oxidized at different sites and the lack of stability for purification or reference standard synthesis. We describe the characterization of the oxidized heteroatoms of the 2-aminothiazole group via gas-phase ion-molecule reactions (GPIMR) in a modified linear quadrupole ion trap mass spectrometer. The GPIMR reagents used were dimethyl disulfide, tert-butyl peroxide, and tri(dimethylamino)borane. Each reagent was introduced into the ion trap through the helium line and was allowed to react with the protonated metabolites. The ionic ion-molecule reaction products and their fragmentation profiles were compared with the profiles of the ionic ion-molecule reaction products of protonated reference compounds that had specific heteroatom functionalities. The oxidized 2-aminothiazole metabolite of 2-ATBA showed a similar GPIMR profile to that of the reference compounds with a tertiary N-oxide functionality and distinct from the profiles of the reference compounds with N-aryl hydroxylamine, nitroso, or pyridine N-oxide functionalities. This study demonstrates the feasibility of fingerprinting the chemical nature of oxidized nitrogen functional groups via GPIMR profiling for metabolite structure elucidation.

Footnotes

    • Received November 7, 2014.
    • Accepted December 29, 2014.
  • dx.doi.org/10.1124/dmd.114.061978.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (3)
Drug Metabolism and Disposition
Vol. 43, Issue 3
1 Mar 2015
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Research ArticleArticle

Structure Elucidation by Gas Phase Ion-Molecule Reaction

Minli Zhang, Ryan Eismin, Hilkka Kenttämaa, Hui Xiong, Ye Wu, Doug Burdette and Rebecca Urbanek
Drug Metabolism and Disposition March 1, 2015, 43 (3) 358-366; DOI: https://doi.org/10.1124/dmd.114.061978

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Research ArticleArticle

Structure Elucidation by Gas Phase Ion-Molecule Reaction

Minli Zhang, Ryan Eismin, Hilkka Kenttämaa, Hui Xiong, Ye Wu, Doug Burdette and Rebecca Urbanek
Drug Metabolism and Disposition March 1, 2015, 43 (3) 358-366; DOI: https://doi.org/10.1124/dmd.114.061978
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