Novel 5-azaindole factor VIIa inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 12; pp. 3197 - 3200
• Main Authors: Riggs, Jennifer R., Hu, Huiyong, Kolesnikov, Aleksandr, Leahy, Ellen M., Wesson, Kieron E., Shrader, William D., Vijaykumar, Dange, Wahl, Troy A., Tong, Zhiwei, Sprengeler, Paul A., Green, Michael J., Yu, Christine, Katz, Brad A., Sanford, Ellen, Nguyen, Margaret, Cabuslay, Ronnel, Young, Wendy B.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.06.2006; Elsevier
• Subjects: Amidine; Amidine replacement; Anti-coagulant; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Azaindole; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Factor VIIa; Factor VIIa - antagonists & inhibitors; Factor VIIa - chemistry; Factor VIIa - metabolism; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Pyrrolopyridine; Serine protease; Structure-Activity Relationship; Amidine; Pyrrolopyridine; Azaindole; Serine protease; Amidine replacement; Anti-coagulant; Factor VIIa; Serine endopeptidases; Enzyme; Enzyme inhibitor; Anticoagulant; Inhibitor enzyme complex; X ray diffraction; In vitro; Peptidases; Structure activity relation; Biphenyl derivatives; Organic fluorine compounds; Phenols; Hydrolases; Ureas; Chemical synthesis; Coagulation Factor VIIa
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.03.049

We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1 H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]- succinic acid scaffold. These biaryl amidine-containing compounds suffer from low oral bioavailability. In an attempt to apply the knowledge we have gained from our amidine fVIIa inhibitor parenteral program to an oral program, we began with our 5-amidinobenzimidazole scaffold and replaced the amidine with a less basic 5-azaindole (1 H-pyrrolo[3,2- c]pyridine, 2). The discovery and development of 5-azaindole factor VIIa inhibitors will be described. The discovery and development of 5-azaindole factor VIIa inhibitors will be described.