Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Drug Metabolism & Disposition
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Drug Metabolism & Disposition

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit dmd on Facebook
  • Follow dmd on Twitter
  • Follow ASPET on LinkedIn
Research ArticleArticle

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Xiaoliang Zhuo, Richard A. Hartz, Joanne J. Bronson, Harvey Wong, Vijay T. Ahuja, Vivekana M. Vrudhula, John E. Leet, Stella Huang, John E. Macor and Yue-Zhong Shu
Drug Metabolism and Disposition January 2010, 38 (1) 5-15; DOI: https://doi.org/10.1124/dmd.109.028910
Xiaoliang Zhuo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard A. Hartz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joanne J. Bronson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Harvey Wong
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vijay T. Ahuja
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vivekana M. Vrudhula
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John E. Leet
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stella Huang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John E. Macor
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yue-Zhong Shu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0–7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.

Footnotes

  • ↵1 Current affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.028910

  • CRF
    corticotropin-releasing factor
    CRF-R1
    corticotropin-releasing factor receptor-1
    CRF-R2
    corticotropin-releasing factor receptor-2
    HPA
    hypothalamic-pituitary-adrenal
    BMS-665053
    (S)-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    PDA
    photodiode array
    amu
    atomic mass units
    MS/MS
    tandem mass spectrometry
    P450
    cytochrome P450
    HLM
    human liver microsome
    RLM
    rat liver microsome
    GGT
    γ-glutamyl transpeptidase.

    • Received June 18, 2009.
    • Accepted October 8, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

 

DMD articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Drug Metabolism and Disposition: 38 (1)
Drug Metabolism and Disposition
Vol. 38, Issue 1
1 Jan 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Drug Metabolism & Disposition article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation
(Your Name) has forwarded a page to you from Drug Metabolism & Disposition
(Your Name) thought you would be interested in this article in Drug Metabolism & Disposition.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Xiaoliang Zhuo, Richard A. Hartz, Joanne J. Bronson, Harvey Wong, Vijay T. Ahuja, Vivekana M. Vrudhula, John E. Leet, Stella Huang, John E. Macor and Yue-Zhong Shu
Drug Metabolism and Disposition January 1, 2010, 38 (1) 5-15; DOI: https://doi.org/10.1124/dmd.109.028910

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Xiaoliang Zhuo, Richard A. Hartz, Joanne J. Bronson, Harvey Wong, Vijay T. Ahuja, Vivekana M. Vrudhula, John E. Leet, Stella Huang, John E. Macor and Yue-Zhong Shu
Drug Metabolism and Disposition January 1, 2010, 38 (1) 5-15; DOI: https://doi.org/10.1124/dmd.109.028910
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments.
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • BSEP Function in Suspension Hepatocytes
  • Candesartan glucuronide serves as a CYP2C8 inhibitor
  • Role of AADAC on eslicarbazepine acetate hydrolysis
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About DMD
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Journal of Pharmacology and Experimental Therapeutics
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-009X (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics