CU-2010—A Novel Small Molecule Protease Inhibitor with Antifibrinolytic and Anticoagulant Properties

Abstract

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 (K i , 2 nM), CU-2010 inhibited fibrinolysis comparable to aprotinin (K i , 4 nM) and was ten times more potent than tranexamic acid. CU-2010 also inhibited plasma kallikrein (K i < 1 nM) and factors Xa (K i , 45 nM) and XIa (K i , 18 nM), which was reflected in prolongation of coagulation times and an attenuation of thrombin generation.Conclusion: These findings suggest that CU-2010 has similar antifibrinolytic potency compared to aprotinin, is more potent than tranexamic acid, and possesses some anticoagulant effects.

Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era

“…The molecule had been assed in in-vitro studies and demonstrated a high affinity to plasmin comparable to aprotinin and 10 times more potent than tranexamic acid [28]. The molecule also inhibited kallikrein and coagulation factors Xa and Xia.…”

Plasma Kallikrein Inhibitors in Cardiovascular Disease

“…37,38 Similarly, other plasma kallikrein inhibitors have also shown to have antithrombotic properties in vitro or in animal models of venous and arterial thrombosis ( Table 1). [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] These studies provide strong evidence that although components of the plasma KKS are dispensable for normal hemostasis, they play a central role in pathological thrombus formation.…”

Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines

“…A relatively strong trypsin inhibition was still found for the phenylsulfonyl and cyclohexylsulfamoyl analogues 29 and 31, with K i values of 62 and 21 nM, respectively, which is in the same range as found for the reference compounds 2 and 3 ( Table 2). 25,27 The strong subnanomolar inhibitory potency of compounds 3, 29, and 31 suggested that plasmin should tolerate some P1 modifications, which lead to a generally reduced affinity against all trypsin-like serine proteases. Therefore, additional inhibitors with the longer piperazine-dipropionyl linker have been prepared, which provided slightly more potent inhibitors than the shorter piperazine-diacetyl linker.…”