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
amidoxime prodrug LK-658 of the lead inhibitor
LK-732 is required for justifying further development of these inhibitors.