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 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.
Groebke Zbinden
Katrin
K
F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. katrin.groebke_zbinden@roche.com
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David W
DW
Ackermann
Jean
J
D'Arcy
Allan
A
Kirchhofer
Daniel
D
Ji
Yu-Hua
YH
Tschopp
Thomas B
TB
Wallbaum
Sabine
S
Weber
Lutz
L
D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D005343:Fibrinolytic Agents; D015842:Serine Proteinase Inhibitors; C470025:phenylglycinamide; D013925:Thromboplastin; D015942:Factor VIIa; D005998:Glycine