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Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-Activated Protein Kinase (AMPK)

  • Tim F. Ryder
    Tim F. Ryder
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
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  • Matthew F. Calabrese
    Matthew F. Calabrese
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • Gregory S. Walker
    Gregory S. Walker
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • Kimberly O. Cameron
    Kimberly O. Cameron
    Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
  • Allan R. Reyes
    Allan R. Reyes
    Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
  • Kris A. Borzilleri
    Kris A. Borzilleri
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • Jake Delmore
    Jake Delmore
    Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
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  • Russell Miller
    Russell Miller
    Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
  • Ravi G. Kurumbail
    Ravi G. Kurumbail
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • Jessica Ward
    Jessica Ward
    Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
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  • Daniel W. Kung
    Daniel W. Kung
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • Janice A. Brown
    Janice A. Brown
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • David J. Edmonds
    David J. Edmonds
    Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
  • Heather Eng
    Heather Eng
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
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  • Angela C. Wolford
    Angela C. Wolford
    Medicine Design, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States
  • , and 
  • Amit S. Kalgutkar*
    Amit S. Kalgutkar
    Medicine Design, Pfizer Worldwide Research & Development, Cambridge, Massachusetts 02139, United States
    *Phone: (617)551-3336. E-mail: [email protected]
Cite this: J. Med. Chem. 2018, 61, 16, 7273–7288
Publication Date (Web):July 23, 2018
https://doi.org/10.1021/acs.jmedchem.8b00807
Copyright © 2018 American Chemical Society

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    Abstract

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    Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 13 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 13. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 13 and M1–M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00807.

    • Additional experimental information for: Procedure for plasma protein binding, mass spectra of 13 and M1–M3, comparative HPLC-UV chromatograms and mass spectra for the biochemical and synthetic acyl glucuronides M1–M3, COSY NMR spectra of M1–M3, comparative HSQC NMR spectra of biochemical and synthetic acyl glucuronides M1–M3, degradation kinetics of M1–M3 in deuteriated phosphate buffer (pH 7.4), inhibition of de novo lipogenesis, X-ray data collection and refinement statistics, crystallization and refinement methods (PDF)

    • Molecular formula strings (CSV)

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    Crystal structure coordinates for compounds M1, M2, and M3 will be deposited to the RCSB Protein Data Bank (www.rcsb.org). Authors will release the atomic coordinates and experimental data upon article publication.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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