Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 14; pp. 2319 - 2325
• Main Authors: South, Michael S., Case, Brenda L., Wood, Rhonda S., Jones, Darin E., Hayes, Michael J., Girard, Thomas J., Lachance, Rhonda M., Nicholson, Nancy S., Clare, Michael, Stevens, Anna M., Stegeman, Roderick A., Stallings, William C., Kurumbail, Ravi G., Parlow, John J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 21.07.2003; Elsevier
• Subjects: Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Drug Design; Factor VIIa - antagonists & inhibitors; Factor Xa Inhibitors; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - pharmacology; Indicators and Reagents; Medical sciences; Models, Molecular; Molecular Conformation; Peptide Library; Pharmacology. Drug treatments; Prothrombin - antagonists & inhibitors; Pyrazines - chemical synthesis; Pyrazines - pharmacology; Structure-Activity Relationship; Thrombin - antagonists & inhibitors; Thrombosis - blood; Thrombosis - chemically induced; Trypsin Inhibitors - chemical synthesis; Trypsin Inhibitors - pharmacology; Serine endopeptidases; Enzyme; Lactam; Combinatorial chemistry; Enzyme inhibitor; Pyrazine derivatives; Anticoagulant; Selectivity; In vitro; Modeling; Peptidases; Amidine; Structure activity relation; Carboxylic acid; Chlorine Organic compounds; Molecular model; Hydrolases; Carboxamide; Benzenic compound; Chemical synthesis; Coagulation Factor VIIa; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00410-4

Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor VIIa complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P 2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P 1 and P 3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC 50 against TF/VIIa with >6250× selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for pre-clinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of sub-nanomolar pyrazinone inhibitors 20 of the tissue factor/Factor VIIa complex.