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Research ArticleArticle

Biotransformation of Two β-Secretase Inhibitors Including Ring Opening and Contraction of a Pyrimidine Ring

Anders Lindgren, Göran Eklund, Dominika Turek, Jonas Malmquist, Britt-Marie Swahn, Jörg Holenz, Stefan von Berg, Sofia Karlström and Tjerk Bueters
Drug Metabolism and Disposition May 2013, 41 (5) 1134-1147; DOI: https://doi.org/10.1124/dmd.112.050351
Anders Lindgren
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Göran Eklund
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Dominika Turek
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Jonas Malmquist
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Britt-Marie Swahn
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Jörg Holenz
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Stefan von Berg
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Sofia Karlström
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Tjerk Bueters
Drug Metabolism and Pharmacokinetics (A.L., G.E., T.B.) and Medicinal Chemistry, Central Nervous System and Pain iMed Science (D.T., B.-M.S., J.H., S.v.B., S.K.), Medicinal Chemistry, Respiratory Inflammatory and Autoimmunity iMed Science (S.v.B.), and Global Drug Metabolism and Pharmacokinetics Screening and Profiling, AstraZeneca R&D (J.M.), Novandi Chemistry AB (J.M.), and MetaSafe AB (G.E.), Södertälje, Sweden
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Abstract

Recently, the discovery of the aminoisoindoles as potent and selective inhibitors of β-secretase was reported, including the close structural analogs compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), the latter being recently progressed to the clinic. The biotransformation of (S)-25 was investigated in vitro and in vivo in rat, rabbit, and human and compared with AZD3839 to further understand the metabolic fate of these compounds. In vitro, CYP3A4 was the major responsible enzyme and metabolized both compounds to a large extent in the commonly shared pyridine and pyrimidine rings. The main proposed metabolic pathways in various in vitro systems were N-oxidation of the pyridine and/or pyrimidine ring and conversion to 4-pyrimidone and pyrimidine-2,4-dione. Both compounds were extensively metabolized, and more than 90% was excreted in feces after intravenous administration of radiolabeled compound to the rat. Here, the main pathways were N-oxidation of the pyridine and/or pyrimidine ring and a ring contraction of the pyrimidine ring into an imidazole ring. Ring-contracted metabolites accounted for 25% of the total metabolism in the rat for (S)-25, whereas the contribution was much smaller for AZD3839. This metabolic pathway was not foreseen on the basis of the obtained in vitro data. In conclusion, we discovered an unusual metabolic pathway of aryl-pyrimidine–containing compounds by a ring-opening reaction followed by elimination of a carbon atom and a ring closure to form an imidazole ring.

Footnotes

    • Received November 26, 2012.
    • Accepted March 1, 2013.
  • dx.doi.org/10.1124/dmd.112.050351.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (5)
Drug Metabolism and Disposition
Vol. 41, Issue 5
1 May 2013
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Research ArticleArticle

Biotransformation of Pyrimidine Ring

Anders Lindgren, Göran Eklund, Dominika Turek, Jonas Malmquist, Britt-Marie Swahn, Jörg Holenz, Stefan von Berg, Sofia Karlström and Tjerk Bueters
Drug Metabolism and Disposition May 1, 2013, 41 (5) 1134-1147; DOI: https://doi.org/10.1124/dmd.112.050351

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Research ArticleArticle

Biotransformation of Pyrimidine Ring

Anders Lindgren, Göran Eklund, Dominika Turek, Jonas Malmquist, Britt-Marie Swahn, Jörg Holenz, Stefan von Berg, Sofia Karlström and Tjerk Bueters
Drug Metabolism and Disposition May 1, 2013, 41 (5) 1134-1147; DOI: https://doi.org/10.1124/dmd.112.050351
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