The invention relates to a new antithrombotic compound, a pharmaceutical composition containing the compound as an active ingredient, as well as the use of said compound for the manufacture of medicaments.
Acute myocardial infarction, ischemia and stroke are caused by the formation of an occlusive thrombus in an atherosclerotic coronary artery. The arterial thrombus is formed by blood platelets (thrombocytes) aggregating with (increased levels of) fibrinogen. This process is associated with an excited state and imbalance of the coagulation system in which fibrinogen is cleaved into fibrin clots. Intervention in one of these primary and secondary haemostatic pathways is essential in the treatment of (arterial) thrombosis.
Serine proteases are enzymes which play an important role in the blood coagulation cascade. Members of this group of proteases are for example thrombin, trypsin, factors VIIa, IXa, Xa, XIa, XIIa, and protein C. Thrombin is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which are cross-linked to form an insoluble gel. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in haemostasis and thrombus formation. Factor Xa catalyzes the conversion of prothrombin into thrombin. Inhibition of factor Xa effectively results in inhibition of the coagulation of blood.
Platelet aggregation is triggered by several activators, not only by thrombin, but also by ADP, collagen and epinephrin. In all cases, the final common pathway leading to platelet aggregation is binding of fibrinogen to its receptor, the key membrane glycoprotein complex GPIIb/IIIa. Therefore, inhibition of fibrinogen binding to this protein is considered a very effective way of inhibiting platelet aggregation for the prevention of (arterial) thrombus formation and the treatment of thrombotic disorders.
GPIIb/IIIa (αIIbβ3) is a surface receptor belonging to the integrin family. Integrins are composed of two chains, an α subunit and a β subunit, which are held together by noncovalent bonds in a calcium dependent manner. GPIIb constitutes the α subunit (αIIb) with divalent cation binding domains, whereas GPIIIa is a protypical β subunit (β3). Integrins have been isolated from cells throughout the body and are mediators of cell-cell and cell-substrate adhesion and signaling. There are three binding sites on GPIIb/IIIa, one that recognizes the amino sequence Arg-Gly-Asp (RGD binding site), another that recognizes Lys-Gln-Ala-Gly-Asp (KQAGD binding site) and one that recognizes Lys-Gly-Asp (KGD binding site).
On each circulating platelet, there are 35,000 to 100,000 GPIIb/IIIa complexes; most are distributed on the platelet surface, with a smaller pool in an internal reserve. The GPIIb/IIIa complex does not interact with its plasma ligands until platelets have been activated by exogenous agonists such as ADP or thrombin. When this occurs, an inside-out signal is generated that results in a conformational change in the extracellular portion of the complex that renders the molecule capable of binding fibrinogen and other ligands.
Compounds mimicking the α-chain (RGD) and γ-chain (KQAGDV) fragments of fibrinogen may act as antagonists. Numerous potent GPIIb/IIIa antagonists based on peptidomimetic structures have been described previously.
Some (very) potent examples are Ro 435054, xemilofiban, RWJ 50042,tirofiban and lamifiban. However, a significant number of GPIIb/IIIa antagonists showing excellent potencies and pharmacological profiles in vitro, are not further developed or on hold after having reached late phase clinical trials, due to a lack of consistent control of platelet aggregation and ambiguous pharmacological behavior, (partly) caused by the short half-lives of the compounds. The short half-lives lead to large variations in plasma levels of the free drug and may contribute to interindividual variability in dose response (monitoring therapy is required).
It was further reported by H. Darius in Thromb Res. 2001, 103, S117-S124 that in all large clinical trials with GPIIb/IIIa antagonists the therapeutic effect was only minor and, moreover, even an increased mortality in the glycoprotein IIb/IIIa receptor-antagonist-treated group of patients (orally treated) had been observed. The narrow therapeutic window and limited bioavailability of the drugs, together with the still very limited knowledge about the regulation of the platelet fibrinogen receptor, were considered to be responsible for this therapeutic failure. In conclusion, there is a need for GPIIb/IIIa antagonists having a predictable antithrombotic effect, preferably with a longer half-life (to achieve consistent levels of inhibition of platelet aggregation).