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Chen P, Zhang DW, Li M, Wu Q, Lam YP, Guo Y, Chen C, Bai N, Malhotra S, Li W, O'Connor PB, Fu HZ
Discovery of novel, potent, isosteviol-based antithrombotic agents
Eur J Med Chem (2019) 183:111722.
Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (K-i = 0.015 mu M) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p < 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p < 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p < 0.01 and p < 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents. (C) 2019 Elsevier Masson SAS. All rights reserved.
Publication Date: 2019-12-01.
Last updated on Wednesday, July 08, 2020