Benzimidazole-Based fXa inhibitors with improved thrombin and trypsin selectivity

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 9; pp. 1311 - 1314
• Main Authors: Shaw, Kenneth J., Guilford, William J., Griedel, Brian D., Sakata, Steve, Trinh, Lan, Wu, Shung, Xu, Wei, Zhao, Zuchun, Morrissey, Michael M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06.05.2002; Elsevier
• Subjects: Benzimidazoles - chemistry; Benzimidazoles - metabolism; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Factor Xa Inhibitors; Medical sciences; Pharmacology. Drug treatments; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - metabolism; Thrombin - metabolism; Trypsin - metabolism; Serine endopeptidases; Enzyme; Nitrogen heterocycle; Benzene derivatives; Enzyme inhibitor; Coagulation Factor Xa; Non peptide compound; Thrombin; Anticoagulant; Selectivity; Peptidases; Amidine; Trypsin; Structure activity relation; Benzimidazole derivatives; Piperidine derivatives; Bicyclic compound; Hydrolases; Aromatic compound; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00145-2

Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well. Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring with a nitro group at C-4 and replacement of the naphthylamidine group with either a biphenylamidine or propenylbenzamidine group. Although both of the changes improved potency against fXa, selectivity versus trypsin was achieved by substitution of the propenylbenzamidine group.