Structure–activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 9; pp. 2845 - 2849
• Main Authors: Corte, James R., Fang, Tianan, Pinto, Donald J.P., Han, Wei, Hu, Zilun, Jiang, Xiang-Jun, Li, Yun-Long, Gauuan, Jolicia F., Hadden, Mark, Orton, Darren, Rendina, Alan R., Luettgen, Joseph M., Wong, Pancras C., He, Kan, Morin, Paul E., Chang, Chong-Hwan, Cheney, Daniel L., Knabb, Robert M., Wexler, Ruth R., Lam, Patrick Y.S.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.05.2008; Elsevier
• Subjects: Administration, Oral; Animals; Anthranilamide; Antithrombin III - administration & dosage; Antithrombin III - chemical synthesis; Antithrombin III - pharmacokinetics; Arteriovenous Shunt, Surgical; Binding Sites; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa; Medical sciences; Models, Animal; ortho-Aminobenzoates - chemistry; Pharmacology. Drug treatments; Piperidines - chemistry; Pyridones - chemistry; Rabbits; Serine Proteinase Inhibitors - administration & dosage; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - pharmacokinetics; Structure-Activity Relationship; Thrombosis - drug therapy; Thrombosis - etiology; Factor Xa; Anthranilamide; Intravenous administration; Nitrogen heterocycle; Lactam; Rabbit; Cardiovascular disease; Coagulation Factor Xa; Anticoagulant; Modeling; Pyridine derivatives; Vascular disease; Structure activity relation; Chlorine Organic compounds; Molecular model; Antithrombotic agent; Dog; Human; Fissipedia; Carnivora; Pyridone derivatives; Serine endopeptidases; Enzyme; Benzene derivatives; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Bioavailability; Lagomorpha; In vitro; Thrombosis; Peptidases; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Hydrolases; Carboxamide; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.03.092

Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.