VE-1902-A direct thrombin inhibitor with reversible covalent mechanism of action shows efficacy with reduced bleeding in rodent models of thrombosis.

Autor: Sivaraja M; Verseon Corporation, Fremont, CA, United States of America. Electronic address: msivaraja@verseon.com., Clemens DM; Verseon Corporation, Fremont, CA, United States of America., Sizikov S; Verseon Corporation, Fremont, CA, United States of America., Dash S; Verseon Corporation, Fremont, CA, United States of America., Xu C; Verseon Corporation, Fremont, CA, United States of America., Rienzo M; Verseon Corporation, Fremont, CA, United States of America., Yang B; Verseon Corporation, Fremont, CA, United States of America., Ryan M; Verseon Corporation, Fremont, CA, United States of America., Chattopadhyay M; Verseon Corporation, Fremont, CA, United States of America., Igoudin L; Verseon Corporation, Fremont, CA, United States of America., Chang SS; Verseon Corporation, Fremont, CA, United States of America., Keutzer S; Verseon Corporation, Fremont, CA, United States of America., Zalicki P; Verseon Corporation, Fremont, CA, United States of America., Estiarte MA; Verseon Corporation, Fremont, CA, United States of America., Shiau TP; Verseon Corporation, Fremont, CA, United States of America., Short KM; Verseon Corporation, Fremont, CA, United States of America., Williams DC; Verseon Corporation, Fremont, CA, United States of America., Datta A; Verseon Corporation, Fremont, CA, United States of America., Pozzi N; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, United States of America., Di Cera E; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, United States of America., Gibson CM; TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States of America., Fox KAA; Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom., Kita DB; Verseon Corporation, Fremont, CA, United States of America.
Jazyk: angličtina
Zdroj: Thrombosis research [Thromb Res] 2020 Jun; Vol. 190, pp. 112-121. Date of Electronic Publication: 2020 Apr 19.
DOI: 10.1016/j.thromres.2020.04.020
Abstrakt: Introduction: High incidence of bleeding events remains a key risk for patients taking anticoagulants, especially those in need of long-term combination therapy with antiplatelet agents. As a consequence, patients may not receive clinically indicated combination antithrombotic therapy. Here, we report on VE-1902, a member of a novel class of precision oral anticoagulants (PROACs) that combines effective anticoagulation with reduced bleeding in preclinical testing.
Methods and Results: Acting through covalent, reversible active-site modification of thrombin similar to a previously described molecule [1], VE-1902 shows potency and selectivity for thrombin inhibition in human plasma comparable to clinically relevant direct thrombin inhibitors (DTI) such as argatroban and dabigatran (thrombin generation assay ETP EC 50  = 1.3 μM compared to 0.36 μM and 0.31 μM for argatroban and dabigatran; >100-fold selectivity against related serine proteases). Unlike the current anticoagulants, VE-1902 does not significantly inhibit thrombin-mediated platelet activation in in vivo models of thrombosis. In the thrombin generation assay, the compound inhibits thrombin formation without significantly delaying the initiation phase of the clotting cascade. These features are possibly responsible for the observed reduced bleeding in tail bleeding and saphenous vein bleeding models. Consistent with this novel pharmacological profile, VE-1902 shows efficacious anticoagulation in several fibrin-driven animal models of thrombosis (arteriovenous shunt, venous stasis thrombosis, and thrombin-induced thromboembolism models), whereas it does not significantly prevent arterial occlusion in the platelet dependent FeCl 3 model.
Conclusions: By leaving platelet activation following vascular injury mostly unaffected, VE-1902, and the PROACs more generally, represent a new generation of precision anticoagulants with reduced bleeding risk.
Competing Interests: Declaration of competing interest E.D.C. has a financial interest in Verseon Corporation.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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