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Research ArticleArticle

Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

Milu T. Cherian, Lei Yang, Sergio C. Chai, Wenwei Lin and Taosheng Chen
Drug Metabolism and Disposition November 2016, 44 (11) 1759-1770; DOI: https://doi.org/10.1124/dmd.116.071993
Milu T. Cherian
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Lei Yang
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Sergio C. Chai
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Wenwei Lin
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Taosheng Chen
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Abstract

The constitutive androstane receptor (CAR) regulates the expression of genes involved in drug metabolism and other processes. A specific inhibitor of CAR is critical for modulating constitutive CAR activity. We recently described a specific small-molecule inhibitor of CAR, CINPA1 (ethyl (5-(diethylglycyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate), which is capable of reducing CAR-mediated transcription by changing the coregulator recruitment pattern and reducing CAR occupancy at the promoter regions of its target genes. In this study, we showed that CINPA1 is converted to two main metabolites in human liver microsomes. By using cell-based reporter gene and biochemical coregulator recruitment assays, we showed that although metabolite 1 was very weak in inhibiting CAR function and disrupting CAR-coactivator interaction, metabolite 2 was inactive in this regard. Docking studies using the CAR ligand-binding domain structure showed that although CINPA1 and metabolite 1 can bind in the CAR ligand-binding pocket, metabolite 2 may be incapable of the molecular interactions required for binding. These results indicate that the metabolites of CINPA1 may not interfere with the action of CINPA1. We also used in vitro enzyme assays to identify the cytochrome P450 enzymes responsible for metabolizing CINPA1 in human liver microsomes and showed that CINPA1 was first converted to metabolite 1 by CYP3A4 and then further metabolized by CYP2D6 to metabolite 2. Identification and characterization of the metabolites of CINPA1 enabled structure-activity relationship studies of this family of small molecules and provided information to guide in vivo pharmacological studies.

Footnotes

    • Received June 3, 2016.
    • Accepted August 11, 2016.
  • This research was supported by ALSAC, St. Jude Children’s Research Hospital, the National Institutes of Health National Institute of General Medical Sciences [Grants R01GM086415, R01GM110034, and R35GM118041], and the National Institutes of Health National Cancer Institute [Grant P30CA21765].

  • dx.doi.org/10.1124/dmd.116.071993.

  • ↵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 (11)
Drug Metabolism and Disposition
Vol. 44, Issue 11
1 Nov 2016
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Research ArticleArticle

Structure and Function of CINPA1 Metabolites

Milu T. Cherian, Lei Yang, Sergio C. Chai, Wenwei Lin and Taosheng Chen
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1759-1770; DOI: https://doi.org/10.1124/dmd.116.071993

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Research ArticleArticle

Structure and Function of CINPA1 Metabolites

Milu T. Cherian, Lei Yang, Sergio C. Chai, Wenwei Lin and Taosheng Chen
Drug Metabolism and Disposition November 1, 2016, 44 (11) 1759-1770; DOI: https://doi.org/10.1124/dmd.116.071993
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