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 and Characterization of 4-[[4-(2-Butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a Novel Dual Tumor Necrosis Factor-α-Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumatoid Arthritis

Yuhua Zhang, Jun Xu, Jeremy Levin, Martin Hegen, Guangde Li, Heidi Robertshaw, Fionula Brennan, Terri Cummons, Dave Clarke, Nichole Vansell, Cheryl Nickerson-Nutter, Dauphine Barone, Ken Mohler, Roy Black, Jerry Skotnicki, Jay Gibbons, Marc Feldmann, Philip Frost, Glenn Larsen and Lih-Ling Lin
Journal of Pharmacology and Experimental Therapeutics April 2004, 309 (1) 348-355; DOI: https://doi.org/10.1124/jpet.103.059675
Yuhua Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jun Xu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeremy Levin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Hegen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guangde Li
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heidi Robertshaw
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fionula Brennan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Terri Cummons
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dave Clarke
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nichole Vansell
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cheryl Nickerson-Nutter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dauphine Barone
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ken Mohler
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roy Black
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jerry Skotnicki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jay Gibbons
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marc Feldmann
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip Frost
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glenn Larsen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lih-Ling Lin
  • 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

Tumor necrosis factor (TNF)-α is a well validated therapeutic target for the treatment of rheumatoid arthritis. TNF-α is initially synthesized as a 26-kDa membrane-bound form (pro-TNF) that is cleaved by a Zn-metalloprotease named TNF-α-converting enzyme (TACE) to generate the 17-kDa, soluble, mature TNF-α. TACE inhibitors that prevent the secretion of soluble TNF-α may be effective in treating rheumatoid arthritis (RA) patients. Using a structure-based design approach, we have identified a novel dual TACE/matrix metalloprotease (MMP) inhibitor 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1). This molecule inhibits TACE and several MMPs with nanomolar IC50 values in vitro. In cell-based assays such as monocyte cell lines, human primary monocytes, and human whole blood, it inhibits lipopolysaccharide (LPS)-induced TNF-α secretion at submicromolar concentrations, whereas there is no effect on the TNF-α mRNA level as judged by RNase protection assay. The inhibition of LPS-induced TNF-α secretion is selective because TMI-1 has no effect on the secretion of other proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and IL-8. Importantly, TMI-1 potently inhibits TNF-α secretion by human synovium tissue explants of RA patients. In vivo, TMI-1 is highly effective in reducing clinical severity scores in mouse prophylactic collagen-induced arthritis (CIA) at 5, 10, and 20 mg/kg p.o. b.i.d. and therapeutic CIA model at 100 mg/kg p.o. b.i.d. In summary, TMI-1, a dual TACE/MMP inhibitor, represents a unique class of orally bioavailable small molecule TNF inhibitors that may be effective and beneficial for treating RA.

Footnotes

  • ↵1 These authors contributed equally to this manuscript.

  • DOI: 10.1124/jpet.103.059675.

  • ABBREVIATIONS: RA, rheumatoid arthritis; TNF-α, tumor necrosis factor-α; MMP, matrix metalloproteinase; TACE, tumor necrosis factor-converting enzyme; TMI-1,4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)-thiomorpholinecarboxamide; OA, osteoarthritis; LPS, lipopolysaccharide; CIA, collagen-induced arthritis; FRET, fluorescence-based fluorescence resonance energy transfer; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; IL, interleukin; ELISA, enzyme-linked immunosorbent assay; CFA, complete Freund's adjuvant; PD98059, 2-(2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; CGS-27023, N-hydroxy-2(R)-(4-methoxysulfonyl) (3-picolyl)-(amino-3 methylbutaneamide hydrochloride monohydrate); BMS-275291, (S)-N-[2-mercapto-1-oxo-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)buty]-L-leucyl-N,3-dimethyl-L-valinamide; BAY 12-9566, 4-[4-(chlorophenyl)-phenyl]-4-oxo-2S-(phenylthiomethyl)butanoic acid.

    • Received September 5, 2003.
    • Accepted December 18, 2003.
  • 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: 309 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 1
1 Apr 2004
  • 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 and Characterization of 4-[[4-(2-Butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a Novel Dual Tumor Necrosis Factor-α-Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumat…
(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 and Characterization of 4-[[4-(2-Butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a Novel Dual Tumor Necrosis Factor-α-Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumatoid Arthritis

Yuhua Zhang, Jun Xu, Jeremy Levin, Martin Hegen, Guangde Li, Heidi Robertshaw, Fionula Brennan, Terri Cummons, Dave Clarke, Nichole Vansell, Cheryl Nickerson-Nutter, Dauphine Barone, Ken Mohler, Roy Black, Jerry Skotnicki, Jay Gibbons, Marc Feldmann, Philip Frost, Glenn Larsen and Lih-Ling Lin
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 348-355; DOI: https://doi.org/10.1124/jpet.103.059675

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 and Characterization of 4-[[4-(2-Butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecarboxamide (TMI-1), a Novel Dual Tumor Necrosis Factor-α-Converting Enzyme/Matrix Metalloprotease Inhibitor for the Treatment of Rheumatoid Arthritis

Yuhua Zhang, Jun Xu, Jeremy Levin, Martin Hegen, Guangde Li, Heidi Robertshaw, Fionula Brennan, Terri Cummons, Dave Clarke, Nichole Vansell, Cheryl Nickerson-Nutter, Dauphine Barone, Ken Mohler, Roy Black, Jerry Skotnicki, Jay Gibbons, Marc Feldmann, Philip Frost, Glenn Larsen and Lih-Ling Lin
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 348-355; DOI: https://doi.org/10.1124/jpet.103.059675
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