CU-2010--a novel small molecule protease inhibitor with antifibrinolytic and anticoagulant properties.
BACKGROUND
In cardiac surgery, the contact of blood with the artificial surfaces of the cardiopulmonary bypass results in activation of coagulation, fibrinolysis, and platelets, which is recognized as reason for increased bleeding tendency. Antifibrinolytics like tranexamic acid or the broad-spectrum protease inhibitor aprotinin attenuate this response. The marketing of aprotinin has been suspended after a recent clinical trial suggested increased risks associated with aprotinin. Moreover, aprotinin is a protein of animal origin and has antigenic properties. As a result, alternative antifibrinolytic compounds are desirable.


METHODS
This in vitro study compared the antifibrinolytic efficacy of the synthetic small molecule CU-2010 with aprotinin and tranexamic acid. Antifibrinolytic activity in plasma and whole blood of ten healthy volunteers was examined with a turbidometric method and with tissue factor-activated thromboelastometry (ROTEM; Pentapharm, Munich, Germany). In addition, anticoagulant effects were assessed through measurement of plasma and whole blood clotting times and thrombin generation.


RESULTS
With its high affinity for plasmin (Ki, 2 nM), CU-2010 inhibited fibrinolysis comparable to aprotinin (Ki, 4 nM) and was ten times more potent than tranexamic acid. CU-2010 also inhibited plasma kallikrein (Ki < 1 nM) and factors Xa (Ki, 45 nM) and XIa (Ki, 18nM), which was reflected in prolongation of coagulation times and an attenuation of thrombin generation.


CONCLUSIONS
These findings suggest that CU-2010 has similar antifibrinolytic potency compared to aprotinin, is more potent than tranexamic acid, and possesses some anticoagulant effects.
Dietrich
Wulf
W
Institute for Research in Cardiac Anesthesia, and Department of Hemostasiology, Ludwig Maximilian University, Munich, Germany. wulf.dietrich@tonline.de
Nicklisch
Silke
S
Koster
Andreas
A
Spannagl
Michael
M
Giersiefen
Helmut
H
van de Locht
Andreas
A
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology*; D000933:Antifibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007611:Aprotinin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D007611:Aprotinin