Thrombin indirect inhibitors

The indirect thrombin inhibitors are so-named because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the... 

The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMWH (see above), which act through antithrombin. Hirudin and bivalirudin are bivalent DTIs in that they bind at both the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site. 

Indirect thrombin inhibitors Tobacco, oilseed Ethiopian mustard Human hirudin variant 2 AMT 8,20... 

The direct thrombin inhibitors have theoretical advantages over the indirect anticoagulants that include more predictable dose-responses, and efficacy against clot bound thrombin. With bivalirudin, clinical trials suggest superiority compared with heparin alone and comparable outcomes when... 

Direct thrombin inhibitors Direct FXa inhibitors Indirect FXa inhibitors... 

Of the indirect inhibitors of thrombin are the he-parins and new delivery systems have been improved with a generation of molecules that can be absorbed by the gastrointestinal tract. 

Mectianism of Action A factorXa inhibitor and pentasaccharide that selectively binds to antithrombin, and increases its affinity for factor Xa, thereby inhibiting factor Xa and stopping the blood coagulation cascade. Therapeutic Effect Indirectly prevents formation of thrombin and subsequently the fibrin clot. 

Protein C exerts an antithrombotic effect by inhibiting Factors Va and Villa. In vitro data indicate that it has indirect prohbri-nolytic activity through its abhity to inhibit plasminogen activator inhibitor-1 (PAI-1) and to hmit production of activated throm-bin-activatable-hbrinolysis inhibitor. In vitro data also indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by hmiting thrombin-induced inflammatory responses within the microvascular endothehum. 

Figure 7. Factor Xa targeting in the devdopment of new antithrombotic agents. Both the direct and indirect inhibitors of factor Xa is explored. Ihese agents are also potent inhibitors of thrombin generation at both the plasmatic and cellular sites.

Direct inhibitors of thrombin inactivate fibrin-bound thrombin which may promote thrombus extension (as opposed to heparin which acts indirectly through antithrombin) as follows ... 

A PF3 indirect assay using a synthetic substrate was developed in 1979 by Sandberg and Anderson (S2). This test monitored thrombin production with the substrate S-2238 and claimed to be 10 times more sensitive than the above assay and to be free of EDTA interference. Later Harsialvi and coworkers claimed to improve the technique by adding soybean trypsin inhibitor to better control the reaction (H2). These workers believe this assay can be used for diagnosis of platelet disorders. 

The products of the phospho-aldol reaction, a-functionalised phosphonate esters such as a-hydroxy- and a-aminophosphonates, find widespread application directly or indirectly as precursors to enzyme inhibitors (such as the enzymes renin [6], thrombin [7],EPSP synthase [8], HIV protease [9] and various classes of PTK and PTPs [10]) and phosphate analogues [11], antibiotics [ 12], antiviral agents [ 13], and in nucleotide technology [ 14]. Within each application stereochemistry of the phosphonate is crucial to eliciting the required properties [15]. 

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