Design of selective phenylglycine amide tissue factor/factor VIIa inhibitors

Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue factor/factor VIIa inhibitors with low nanomolar...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-02, Vol.15 (3), p.817-822
Main Authors: Groebke Zbinden, Katrin, Banner, David W., Ackermann, Jean, D’Arcy, Allan, Kirchhofer, Daniel, Ji, Yu-Hua, Tschopp, Thomas B., Wallbaum, Sabine, Weber, Lutz
Format: Article
Language:English
Subjects:
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Drug Design
Factor VIIa - antagonists & inhibitors
Fibrinolytic Agents - chemical synthesis
Fibrinolytic Agents - pharmacology
Glycine - analogs & derivatives
Glycine - chemical synthesis
Glycine - pharmacology
Humans
Kinetics
Medical sciences
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Serine Proteinase Inhibitors - chemical synthesis
Structure-Activity Relationship
Thromboplastin - antagonists & inhibitors
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Summary:Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue factor/factor VIIa inhibitors with low nanomolar affinity and good selectivity against other serine proteases of the coagulation cascade were designed. Proof of concept experiments have shown that tissue factor/factor VIIa inhibitors have antithrombotic activity without enhancing bleeding propensity. Starting from lead compounds generated by a biased combinatorial approach, phenylglycine amide tissue factor/factor VIIa inhibitors with low nanomolar affinity and good selectivity against other serine proteases of the coagulation cascade were designed, using the guidance of X-ray structural analysis and molecular modelling.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.10.092