Dose-dependent antithrombotic activity of an orally active tissue factor/factor VIIa inhibitor without concomitant enhancement of bleeding propensity.
The discovery of a highly potent and selective tissue factor/factor VIIa inhibitor is described. Upon oral administration of its double prodrug in the guinea pig, a dose-dependent antithrombotic effect is observed in an established model of arterial thrombosis without prolonging bleeding time. The pharmacodynamic properties of this selective inhibitor are compared to the behaviour of a mixed factor VIIa/factor Xa inhibitor.
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
Hilpert
Kurt
K
Himber
Jacques
J
Lavé
Thierry
T
Riederer
Markus A
MA
Stahl
Martin
M
Tschopp
Thomas B
TB
Obst-Sander
Ulrike
U
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D001760:Bleeding Time; D019774:Blood Coagulation Factor Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control
D000925:Anticoagulants; D019774:Blood Coagulation Factor Inhibitors; D011355:Prodrugs; D013925:Thromboplastin; D015942:Factor VIIa