The discovery of fluoropyridine-based inhibitors of the factor VIIa/TF complex—Part 2

• Published in: Bioorganic & medicinal chemistry letters 2006-02, Vol.16 (4), p.1060-1064
• Main Authors: Kohrt, Jeffrey T., Filipski, Kevin J., Cody, Wayne L., Cai, Cuiman, Dudley, Danette A., Van Huis, Chad A., Willardsen, J. Adam, Narasimhan, Lakshmi S., Zhang, Erli, Rapundalo, Stephen T., Saiya-Cork, Kamlai, Leadley, Robert J., Edmunds, Jeremy J.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Factor VIIa - antagonists & inhibitors; Factor VIIa inhibitor; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Serine protease inhibitor; Structure-Activity Relationship; Thromboplastin - antagonists & inhibitors; Tissue factor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.10.076

The activated factor VII/tissue factor complex (FVIIa/TF) is known to play a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. A fluoropyridine-based series of FVIIa/TF inhibitors was discovered which utilized a diisopropylamino group for binding in the S2 and S3 binding pockets of the active site of the enzyme complex. In this series, an enhancement in binding affinity was observed by substitution at the 5-position of the hydroxybenzoic acid sidechain. An X-ray crystal structure indicates that amides at this position may increase inhibitor binding affinity through interactions with the S1′/S2′ pocket.