Thromb Haemost 2005; 93(03): 437-442
DOI: 10.1160/TH04-10-0676
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold in two rat venous thrombosis models

Luka Peternel
1   Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia
3   Faculty of Medicine, Institute of Pharmacology and Experimental Toxicology, Ljubljana, Slovenia
,
Mojca Stegnar
2   University Medical Centre, Department of Angiology, Ljubljana, Slovenia
,
Gorazd Drevenšek
3   Faculty of Medicine, Institute of Pharmacology and Experimental Toxicology, Ljubljana, Slovenia
,
Metka V. Budihna
3   Faculty of Medicine, Institute of Pharmacology and Experimental Toxicology, Ljubljana, Slovenia
,
Mojca Božič
2   University Medical Centre, Department of Angiology, Ljubljana, Slovenia
,
Anamarija Zega
4   Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ljubljana, Slovenia
,
Anton Štalc
1   Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia
,
Manica Černe
1   Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia
,
Uroš Urleb
1   Lek Pharmaceuticals d.d., Drug Discovery, Ljubljana, Slovenia
4   Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ljubljana, Slovenia
› Institutsangaben
Financial support: The financial support of this work by Lek Pharmaceuticals d.d (Ljubljana, Slovenia) and by the Ministry of Education, Science and Sport of the Republic of Slovenia (Grant No L3–5084) is gratefully acknowledged.
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Publikationsverlauf

Received 20. Oktober 2004

Accepted after revision 10. Februar 2004

Publikationsdatum:
14. Dezember 2017 (online)

Summary

The antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold (LK-732, LK-639 and LK-731) and their amidoxime prodrugs (LK-658, LK-633 and LK-730) was studied in comparison to argatroban and nadroparin in two rat models of venous thrombosis, induced either by complete stasis combined with hypercoagulability (model 1) or by partial stasis combined with vessel injury (model 2). In initial experiments LK-732 was established as the most promising antithrombotic of the LK inhibitors and as such was further tested. In model 1, intravenous bolus administration of LK-732 produced a dose-dependent inhibition of thrombus formation with an ID50 value of 1.3 mg/kg. This ID50 value was approximately four times higher than the ID50 value of argatroban (0.3 mg/kg; p=0.011). However, in model 2, LK-732 and argatroban decreased thrombus weight by 50% at similar ID50 values (3.8 mg/kg vs 3.0 mg/kg, respectively; p=0.726). The ex vivo anticoagulant effect of LK-732 was substantially weaker compared to argatroban at doses that produced comparable antithrombotic effects. After subcutaneous administration, in vivo thrombus weight reduction of LK inhibitors (10 mg/kg) ranged between 22 to 48%. However, their oral antithrombotic effect at a dose of 30 mg/kg was rather low. LK amidoxime prodrugs failed to produce a substantial antithrombotic effect after subcutaneous (10 mg/ kg) as well as after oral administration (30 mg/kg). In conclusion, thrombin inhibitors built on the azaphenylalanine scaffold represent a new group of intravenously effective antithrombotics. However, optimisation of the oral antithrombotic effect of amid-oxime prodrug LK-658 of the lead inhibitor LK-732 is required for justifying further development of these inhibitors.