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 ArticleArticle

Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3

Shaker A. Mousa, Jeffrey M. Bozarth, William Lorelli, Mark S. Forsythe, Martin J. M. C. Thoolen, Andrew M. Slee, Thomas M. Reilly and Paul A. Friedman
Journal of Pharmacology and Experimental Therapeutics September 1998, 286 (3) 1277-1284;
Shaker A. Mousa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeffrey M. Bozarth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William Lorelli
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark S. Forsythe
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin J. M. C. Thoolen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew M. Slee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas M. Reilly
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul A. Friedman
  • 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

Recent advances in the development of i.v. platelet glycoprotein αIIb/β3 integrin (GPIIb/IIIa) antagonists led to the development of either a class of small-molecular-weight antagonists with a short to ultra-short duration of antiplatelet effects (Integrelin, Tirofiban, DMP728) or a very long-acting antagonist (ReoPro). Thus the present study was undertaken to characterize the antiplatelet efficacy of a small-molecule GPIIb/IIIa antagonist, DMP754/XV459, and to determine its platelet GPIIb/IIIa receptor binding profiles. DMP754, upon its conversion with esterases to its free acid form XV459, and XV459 itself, demonstrated high potency (IC50 = 0.030–0.060 μM) in inhibiting human platelet aggregation induced by ADP (100 μM), thrombin receptor agonist peptide (10 μM) or collagen (20 μg/ml) in citrate or heparin. Maximal platelet aggregation inhibition was achieved at 50 to ≥80% receptor occupancy, depending on the agonist used. Both XV459 and c7E3 bind with high affinity to either activated human platelets (Kd = 0.0008 and 0.0091 μM, respectively) or unactivated human platelets (Kd = 0.0025 and 0.0092 μM, respectively). XV459 demonstrated tight association with human, baboon and (to a lesser extent) canine platelets (t½ of dissociation = 7 ± 0, 8 ± 1 and 1.4 ± 0.1 minutes, respectively). Both c7E3 and XV459 associate tightly with slower dissociation rates to unactivated human platelets. XV459 represents a potent antiplatelet agent in inhibiting platelet aggregation along with offering high affinity and a relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that might allow for once-a-day p.o. dosage.

Footnotes

  • Send reprint requests to: Shaker A. Mousa, Ph.D., MBA, FACC, Du Pont Pharmaceutical Company, Exp. Station, E400/3470, Wilmington, DE 19880-0400. Email:shaker.a.mousa{at}dupontpharma.com

  • Abbreviations:
    GPIIb/IIIa
    glycoprotein αIIb/β3 integrin
    RGD
    Arg-Gly-Asp
    PRP
    platelet-rich plasma
    PPP
    platelet-poor plasma
    TRAP
    thrombin receptor agonist peptide
    P.O.
    Oral
    • Received May 15, 1997.
    • Accepted May 6, 1998.
  • 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
Vol. 286, Issue 3
1 Sep 1998
  • Table of Contents
  • 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.
Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3
(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 ArticleArticle

Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3

Shaker A. Mousa, Jeffrey M. Bozarth, William Lorelli, Mark S. Forsythe, Martin J. M. C. Thoolen, Andrew M. Slee, Thomas M. Reilly and Paul A. Friedman
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1277-1284;

Citation Manager Formats

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

Share
Research ArticleArticle

Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3

Shaker A. Mousa, Jeffrey M. Bozarth, William Lorelli, Mark S. Forsythe, Martin J. M. C. Thoolen, Andrew M. Slee, Thomas M. Reilly and Paul A. Friedman
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1277-1284;
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
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • PST3093 Stimulates SERCA2a and Improves Cardiac Function
  • CRV431 Decreases Liver Fibrosis and Tumor Development
  • Is Hydroxylamine-Induced Cytotoxicity a Valid Marker for Hypersensitivity Reactions to Sulfamethoxazole in Human Immunodeficiency Virus-Infected Individuals?
Show more Article

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