1. Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity.
- Author
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Sun X, Hong Z, Liu M, Guo S, Yang D, Wang Y, Lan T, Gao L, Qi H, Gong P, and Liu Y
- Subjects
- Animals, Anticoagulants pharmacology, Anticoagulants therapeutic use, Binding Sites, Blood Coagulation drug effects, Catalytic Domain, Factor Xa metabolism, Factor Xa Inhibitors pharmacology, Factor Xa Inhibitors therapeutic use, Humans, Molecular Docking Simulation, Protein Binding, Pyrazoles pharmacology, Pyrazoles therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Rabbits, Rats, Structure-Activity Relationship, Venous Thrombosis drug therapy, Anticoagulants chemical synthesis, Drug Design, Factor Xa chemistry, Factor Xa Inhibitors chemical synthesis, Pyrazoles chemistry, Pyridines chemistry
- Abstract
A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC
50 (FXa) value of 0.14μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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