Amido-(propyl and allyl)-hydroxybenzamidines : Development of achiral inhibitors of factor Xa

• Published in: Bioorganic & medicinal chemistry letters Vol. 10; no. 3; pp. 217 - 221
• Main Authors: YONG GONG, PAULS, H. W, SPADA, A. P, CZEKAJ, M, GUYAN LIANG, CHU, V, COLUSSI, D. J, BROWN, K. D, JINGBO GAO
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 07.02.2000
• Subjects: Animals; Benzamidines - chemical synthesis; Benzamidines - chemistry; Benzamidines - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa Inhibitors; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Serine endopeptidases; Enzyme; Coagulation Factor Xa; Anticoagulant; Selectivity; In vitro; Modeling; Peptidases; Amidine; Structure activity relation; Biphenyl derivatives; Molecular model; Phenols; Hydrolases; Carboxamide; Benzenic compound; Aromatic compound; Inhibitor; Chemical synthesis; Ethylenic compound
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(99)00673-3

The design, synthesis and SAR of amido-(propyl and allyl)-hydroxybenzamidine coagulation factor Xa inhibitors is described. These achiral inhibitors are selective for fXa vis a vis structurally related serine proteases and are readily prepared in 6-7 linear steps. The most potent member 9j (fXa Ki = 0.75 nM) is selective (>1000-fold) and an effective anticoagulant in mammalian plasma.