Development of a novel class of potent and selective FIXa inhibitors

[Display omitted] Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2015-11, Vol.25 (21), p.4945-4949
Main Authors: Zhang, Ting, Andre, Patrick, Bateman, Thomas J., Chen, Yi-Heng, Desai, Kunal, Ellsworth, Kenneth, Geissler, Wayne M., Guo, Liangqin, Hruza, Alan, Jian, Tianying, Meng, Dongfang, Parker, Dann L., Qian, Xiaoxia, Reichert, Paul, Sherer, Edward C., Shu, Min, Smith, Cameron J., Sonatore, Lisa M., Tschirret-Guth, Richard, Nolting, Andrew F., Orr, Robert, Campeau, Louis-Charles, Araki, Kazuto, Nishimura, Teruyuki, Sakurada, Isao, Wood, Harold B.
Format: Article
Language:English
Subjects:
Administration, Oral
Amines - chemical synthesis
Amines - chemistry
Amines - pharmacology
Animals
Benzimidazole
Biological Availability
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Factor IXa - antagonists & inhibitors
Factor IXa - metabolism
FIXa inhibitor
Humans
Models, Molecular
Molecular Structure
Rats
Structure based drug design
Structure-Activity Relationship
TGA
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Summary:[Display omitted] Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.04.057