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Design, synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 May 15; Vol. 25 (10), pp. 2800-2810. Date of Electronic Publication: 2017 Mar 29. - Publication Year :
- 2017
-
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 <subscript>50</subscript> (FXa) value of 0.14μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 25
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28389110
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.03.055