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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Identification of R146225 as a Novel, Orally Active Inhibitor of Interleukin-5 Biosynthesis

Jean Van Wauwe, Frans Aerts, Marina Cools, Frederik Deroose, Eddy Freyne, Jan Goossens, Bart Hermans, Jean Lacrampe, Heidi Van Genechten, Frans Van Gerven and Greta Van Nyen
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 655-661;
Jean Van Wauwe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frans Aerts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marina Cools
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frederik Deroose
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eddy Freyne
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jan Goossens
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bart Hermans
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean Lacrampe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heidi Van Genechten
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frans Van Gerven
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Greta Van Nyen
  • 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

Interleukin (IL)-5 regulates the growth, differentiation, and activation of eosinophils. When activated, eosinophils release an array of proinflammatory and cytotoxic products and act as prominent effector cells in the process of allergic inflammation. Depriving eosinophils of IL-5 may therefore represent a viable approach to treat allergic disorders. This study describes the identification of R146225, a novel six-substituted azauracil derivative, as a potent, orally active inhibitor of IL-5 biosynthesis, capable of reducing pulmonary eosinophilia in mice. In vitro, R146225 inhibited IL-5 protein formation by activated human whole blood (IC50 = 34 nM), human peripheral blood mononuclear cells (IC50 = 24 nM), and murine spleen cells (IC50 = 6 nM). In contrast, the compound enhanced generation of interferon-γ and had little or no inhibitory effect on the production of IL-2 and IL-4. Reverse transcription-polymerase chain reaction analysis of stimulated whole blood cells indicated R146225's ability to down-regulate IL-5 mRNA expression. In vivo p.o. administration of R146225 (2.5 mg/kg) to mice before an i.v. anti-CD3 antibody challenge reduced IL-5 but enhanced interferon-γ serum levels, without affecting IL-2 and IL-4 production. Analogous to the in vitro results, R146225 suppressed splenic IL-5 mRNA expression, while message levels of the other cytokines remained unchanged. Moreover, p.o. dosing of R146225 (0.6–2.5 mg/kg) dose dependently reduced the pulmonary accumulation of eosinophils induced in mice by an intranasal instillation ofCryptococcus neoformans. Based on these data, R146225 may be useful in the therapy of eosinophil-driven allergic conditions.

Footnotes

  • Send reprint requests to: Jean Van Wauwe, Janssen Research Foundation, Turnhoutseweg 30, 2340 Beerse, Belgium. E-mail:jvwauwe{at}janbe.jnj.com

  • Abbreviations:
    IL
    interleukin
    PHA
    phytohemagglutinin
    PBMC
    peripheral blood mononuclear cell
    CFU
    colony-forming unit
    ELISA
    enzyme-linked immunosorbent assay
    IFN-γ
    interferon-γ
    PCR
    polymerase chain reaction
    Th cell
    helper T cell
    • Received April 19, 2000.
    • Accepted July 4, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics 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.
Identification of R146225 as a Novel, Orally Active Inhibitor of Interleukin-5 Biosynthesis
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Identification of R146225 as a Novel, Orally Active Inhibitor of Interleukin-5 Biosynthesis

Jean Van Wauwe, Frans Aerts, Marina Cools, Frederik Deroose, Eddy Freyne, Jan Goossens, Bart Hermans, Jean Lacrampe, Heidi Van Genechten, Frans Van Gerven and Greta Van Nyen
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 655-661;

Citation Manager Formats

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

Identification of R146225 as a Novel, Orally Active Inhibitor of Interleukin-5 Biosynthesis

Jean Van Wauwe, Frans Aerts, Marina Cools, Frederik Deroose, Eddy Freyne, Jan Goossens, Bart Hermans, Jean Lacrampe, Heidi Van Genechten, Frans Van Gerven and Greta Van Nyen
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 655-661;
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

  • Lipopolysaccharide Induces Epithelium- and Prostaglandin E2-Dependent Relaxation of Mouse Isolated Trachea through Activation of Cyclooxygenase (COX)-1 and COX-2
  • Cannabinoid-Mediated Elevation of Intracellular Calcium: A Structure-Activity Relationship
  • Protease-Activated Receptor-2 Peptides Activate Neurokinin-1 Receptors in the Mouse Isolated Trachea
Show more INFLAMMATION AND IMMUNOPHARMACOLOGY

Similar Articles

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

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

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