Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors

[Display omitted] Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2017-06, Vol.27 (11), p.2622-2628
Hauptverfasser:	Sakurada, Isao, Endo, Toshiya, Hikita, Katsuyoshi, Hirabayashi, Tomokazu, Hosaka, Yoshitaka, Kato, Yutaka, Maeda, Yoshitaka, Matsumoto, Shigeki, Mizuno, Takashi, Nagasue, Hiroshi, Nishimura, Teruyuki, Shimada, Shunsuke, Shinozaki, Mikihiko, Taguchi, Keiko, Takeuchi, Katsutoshi, Yokoyama, Tooru, Hruza, Alan, Reichert, Paul, Zhang, Ting, Wood, Harold B., Nakao, Kazunari, Furusako, Shoji
Format:	Artikel
Sprache:	eng
Schlagworte:	60 APPLIED LIFE SCIENCES Aminobenzisoxazole Animals Anticoagulant Azabicyclic ring Binding Sites Blood Coagulation - drug effects Crystallography, X-Ray Dogs Drug Design Drug Evaluation, Preclinical Factor IXa - antagonists & inhibitors Factor IXa - metabolism Factor IXa inhibitor Half-Life Humans Inhibitory Concentration 50 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Isoxazoles - chemistry Isoxazoles - metabolism Isoxazoles - pharmacology Molecular Dynamics Simulation Partial Thromboplastin Time Protein Structure, Tertiary Prothrombin Time Rats Structure based drug design Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2017.03.002