Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 4; pp. 989 - 993
• Main Authors: PENGLIE ZHANG, LIANG BAO, HOLLENBACH, Stanley J, SCARBOROUGH, Robert M, ZHU, Bing-Yan, ZUCKETT, Jingmei F, JIA, Zhaozhong J, WOOLFREY, John, ARFSTEN, Ann, EDWARDS, Susan, SINHA, Uma, HUTCHALEELAHA, Athiwat, LAMBING, Joseph L
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 23-02-2004
• Subjects: Administration, Oral; Amides - chemical synthesis; Amides - pharmacology; Animals; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Factor Xa Inhibitors; Humans; Medical sciences; Molecular Structure; ortho-Aminobenzoates - chemical synthesis; ortho-Aminobenzoates - pharmacology; Pharmacology. Drug treatments; Rabbits; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thrombosis - drug therapy; Rat; Rabbit; Coagulation Factor Xa; Thrombin; Blood plasma; Structure activity relation; Chlorine Organic compounds; Antithrombotic agent; Chemical synthesis; Oxazole derivatives; Human; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Deep vein thrombosis; Bioavailability; Lagomorpha; In vitro; Peptidases; In vivo; Vertebrata; Experimental disease; Mammalia; Animal; Hydrolases; Carboxamide; Benzenic compound; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.11.080

Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 microM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats.