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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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-11, Vol.25 (21), p.4945-4949
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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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Zusammenfassung:	[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