Development of Zafirlukast Analogues for Improved Antithrombotic Activity Through Thiol Isomerase Inhibition
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Le résumé fourni par la source
BACKGROUND: Thiol isomerases play essential and nonredundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the 2 major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, a Food and Drug Administration-approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity. METHODS: Thirty-five ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet activation, aggregation, P-selectin expression, and laser-induced thrombosis in mice and compared with the parent compound. RESULTS: Of the 35 analogues, 12 retained activity, with 1, compound 21, that demonstrated a greater potency than that of ZAF, 5 had a similar potency to that of ZAF, and 6 had a weaker potency. Analogues demonstrated inhibition of platelet aggregation and P-selectin expression as compared with ZAF, consistent with their potencies. ZAF and compound 21 were shown to be reversible inhibitors of thiol isomerases, and not cytotoxic to cultured, lung, liver, and kidney cells. Finally, in an in vivo assessment of thrombus formation, compound 21 was able to significantly inhibit thrombus formation without affecting bleeding times. CONCLUSIONS: A ZAF analogue, compound 21, with properties superior to those of ZAF was synthesized, demonstrating improved inhibition of platelet activation, aggregation, and thrombus formation as compared with the parent ZAF. This approach could yield a promising clinical candidate for treatment and prophylaxis of arterial and venous thrombosis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Development of Zafirlukast Analogues for Improved Antithrombotic Activity Through Thiol Isomerase Inhibition
- Date Crossref
- 01/04/2025
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Western New England University pays non établi dans la noticeUniversité ou école supérieure
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University of Kentucky pays non établi dans la noticeUniversité ou école supérieure
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Baystate Medical Center pays non établi dans la noticeÉtablissement de santé
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Baystate Health pays non établi dans la noticeÉtablissement de santé
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College of Pharmacy and Health Sciences Department of Pharmaceutical and Administrative Sciences pays non établi dans la noticeUniversité ou école supérieure
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School of Biological Sciences Institute for Cardiovascular and Metabolic Research pays non établi dans la noticeUniversité ou école supérieure
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Department of Medicine pays non établi dans la noticeInstitution
Western New England University, University of Kentucky et Baystate Medical Center, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.