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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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Article Information

vol. 44 no. 5 653-664
DOI 
https://doi.org/10.1124/dmd.115.069112
PubMed 
26921386

Published By 
American Society for Pharmacology and Experimental Therapeutics
Print ISSN 
0090-9556
Online ISSN 
1521-009X
History 
  • Received December 21, 2015
  • Accepted February 19, 2016
  • Published online April 1, 2016.

Article Versions

  • Earlier version (February 26, 2016 - 06:27).
  • You are viewing the most recent version of this article.
Copyright & Usage 
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics

Author Information

  1. Su-Er W. Huskey,
  2. Chun-qi Zhu,
  3. Melissa M. Lin1,
  4. Ry R. Forseth,
  5. Helen Gu,
  6. Oliver Simon,
  7. Fabian K. Eggimann,
  8. Matthias Kittelmann,
  9. Alexandre Luneau,
  10. Alexandra Vargas,
  11. Hongmei Li,
  12. Lai Wang,
  13. Heidi J. Einolf,
  14. Jin Zhang,
  15. Sarah Favara,
  16. Handan He, and
  17. James B. Mangold
  1. 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.)
  1. Address correspondence to:
    Su-Er Wu Huskey, Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, One Health Plaza, East Hanover, NJ 07936-1080. E-mail: Su.huskey{at}novartis.com
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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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