Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
    • Special Sections
    • 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
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

Daigen Xu, Steven E. Rowland, Patsy Clark, André Giroux, Bernard Côté, Sébastien Guiral, Myriam Salem, Yves Ducharme, Richard W. Friesen, Nathalie Méthot, Joseph Mancini, Laurent Audoly and Denis Riendeau
Journal of Pharmacology and Experimental Therapeutics September 2008, 326 (3) 754-763; DOI: https://doi.org/10.1124/jpet.108.138776
Daigen Xu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven E. Rowland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patsy Clark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
André Giroux
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bernard Côté
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sébastien Guiral
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Myriam Salem
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yves Ducharme
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard W. Friesen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nathalie Méthot
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph Mancini
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laurent Audoly
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Denis Riendeau
  • 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

Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E2 (PGE2) synthase in the cyclooxygenase pathway. Inhibitors of mPGES-1 may block PGE2 production and relieve inflammatory symptoms. To test the hypothesis, we evaluated the antipyretic and analgesic properties of a novel and selective mPGES-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile], in animal models of inflammation. MF63 potently inhibited the human mPGES-1 enzyme (IC50 = 1.3 nM), with a high degree (>1000-fold) of selectivity over other prostanoid synthases. In rodent species, MF63 strongly inhibited guinea pig mPGES-1 (IC50 = 0.9 nM) but not the mouse or rat enzyme. When tested in the guinea pig and a knock-in (KI) mouse expressing human mPGES-1, the compound selectively suppressed the synthesis of PGE2, but not other prostaglandins inhibitable by nonsteroidal anti-inflammatory drugs (NSAIDs), yet retained NSAID-like efficacy at inhibiting lipopolysaccharide-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. In addition, MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the KI mice or nonhuman primates, although it markedly inhibited PGE2 synthesis in the KI mouse stomach. Our data demonstrate that mPGES-1 inhibition leads to effective relief of both pyresis and inflammatory pain in preclinical models of inflammation and may be a useful approach for treating inflammatory diseases.

Footnotes

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

  • doi:10.1124/jpet.108.138776.

  • ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase; EIA, enzyme immunoassay; EP, E prostanoid receptor; FBS, fetal bovine serum; kb, kilo base; KI, knock-in; LPS, lipopolysaccharide; L/R ratio, weight bearing ratio between left/right forelimbs; MF63, 2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile; MF-tricyclic, 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; MIA, monosodium iodoacetate; mPGES, microsomal prostaglandin E synthase; PG, prostaglandin; 6-keto-PGF1α, 6-keto-prostaglandin F1α; TXB2, thromboxane B2; WT, wild type; IL, interleukin; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide; PCR, polymerase chain reaction; PWL, paw withdrawal latency.

    • Received March 11, 2008.
    • Accepted May 12, 2008.
  • 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.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
  • 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.
MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation
(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, IMMUNOPHARMACOLOGY, AND ASTHMA

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

Daigen Xu, Steven E. Rowland, Patsy Clark, André Giroux, Bernard Côté, Sébastien Guiral, Myriam Salem, Yves Ducharme, Richard W. Friesen, Nathalie Méthot, Joseph Mancini, Laurent Audoly and Denis Riendeau
Journal of Pharmacology and Experimental Therapeutics September 1, 2008, 326 (3) 754-763; DOI: https://doi.org/10.1124/jpet.108.138776

Citation Manager Formats

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

Share
Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

Daigen Xu, Steven E. Rowland, Patsy Clark, André Giroux, Bernard Côté, Sébastien Guiral, Myriam Salem, Yves Ducharme, Richard W. Friesen, Nathalie Méthot, Joseph Mancini, Laurent Audoly and Denis Riendeau
Journal of Pharmacology and Experimental Therapeutics September 1, 2008, 326 (3) 754-763; DOI: https://doi.org/10.1124/jpet.108.138776
Reddit logo Twitter logo Facebook 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

  • PK/PD of Dexamethasone in LPS-Challenged Rats
  • Expression of PAR2 in iKera to Model Atopic Dermatitis
  • Cholesterol Esterification and Acute Lung Injury
Show more Inflammation, Immunopharmacology, and Asthma

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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics