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Research ArticleArticle

Identification of Three Novel Ring Expansion Metabolites of KAE609, a New Spiroindolone Agent for the Treatment of Malaria, in Rats, Dogs, and Humans

Su-Er W. Huskey, Chun-qi Zhu, Melissa M. Lin, Ry R. Forseth, Helen Gu, Oliver Simon, Fabian K. Eggimann, Matthias Kittelmann, Alexandre Luneau, Alexandra Vargas, Hongmei Li, Lai Wang, Heidi J. Einolf, Jin Zhang, Sarah Favara, Handan He and James B. Mangold
Drug Metabolism and Disposition May 2016, 44 (5) 653-664; DOI: https://doi.org/10.1124/dmd.115.069112
Su-Er W. Huskey
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Chun-qi Zhu
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Melissa M. Lin
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Ry R. Forseth
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Helen Gu
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Oliver Simon
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Fabian K. Eggimann
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Matthias Kittelmann
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Alexandre Luneau
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Alexandra Vargas
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Hongmei Li
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Lai Wang
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Heidi J. Einolf
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Jin Zhang
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Sarah Favara
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Handan He
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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James B. Mangold
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey (S.-E.W.H., C.Z., R.R.F., H.G., H.L., L.W., H.J.E., J.Z., S.F., H.H., J.B.M.); Technical Research and Development, Novartis Pharma, East Hanover, NJ (M.M.L.); Novartis Institute for Tropical Diseases, Singapore (O.S.); and Global Discovery Chemistry, Bioreactions Group, Novartis Institutes for BioMedical Research, Basel, Switzerland (F.K.E., M.K., A.L., A.V.)
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Abstract

KAE609 [(1′R,3′S)-5,7′-dichloro-6′-fluoro-3′-methyl-2′,3′,4′,9′-tetrahydrospiro[indoline-3,1′-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. After oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Among the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1,2-acyl shift to form a ring expansion metabolite M37. The in vitro metabolism of KAE609 in hepatocytes was investigated to understand this novel biotransformation. The metabolism of KAE609 was qualitatively similar across the species studied; thus, further investigation was conducted using human recombinant cytochrome P450 enzymes. The ring expansion reaction was found to be primarily catalyzed by cytochrome P450 (CYP) 3A4 yielding M37. M37 was subsequently oxidized to M18 by CYP3A4 and hydroxylated to M23 primarily by CYP1A2. Interestingly, M37 was colorless, whereas M18 and M23 showed orange yellow color. The source of the color of M18 and M23 was attributed to their extended conjugated system of double bonds in the structures.

Footnotes

    • Received December 21, 2015.
    • Accepted February 19, 2016.
  • ↵1 Current affiliation: Merck Research Laboratories, Rahway, NJ

  • All authors are employees of Novartis. The authors have no other relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

  • dx.doi.org/10.1124/dmd.115.069112.

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

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (5)
Drug Metabolism and Disposition
Vol. 44, Issue 5
1 May 2016
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Research ArticleArticle

Ring Expansion Metabolites of KAE609 (a Spiroindolone)

Su-Er W. Huskey, Chun-qi Zhu, Melissa M. Lin, Ry R. Forseth, Helen Gu, Oliver Simon, Fabian K. Eggimann, Matthias Kittelmann, Alexandre Luneau, Alexandra Vargas, Hongmei Li, Lai Wang, Heidi J. Einolf, Jin Zhang, Sarah Favara, Handan He and James B. Mangold
Drug Metabolism and Disposition May 1, 2016, 44 (5) 653-664; DOI: https://doi.org/10.1124/dmd.115.069112

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Research ArticleArticle

Ring Expansion Metabolites of KAE609 (a Spiroindolone)

Su-Er W. Huskey, Chun-qi Zhu, Melissa M. Lin, Ry R. Forseth, Helen Gu, Oliver Simon, Fabian K. Eggimann, Matthias Kittelmann, Alexandre Luneau, Alexandra Vargas, Hongmei Li, Lai Wang, Heidi J. Einolf, Jin Zhang, Sarah Favara, Handan He and James B. Mangold
Drug Metabolism and Disposition May 1, 2016, 44 (5) 653-664; DOI: https://doi.org/10.1124/dmd.115.069112
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