Direct thrombin inhibitors: Patents 2002–2012 (Review)

Abstract

Acute vascular diseases and other thromboses of the blood system constitute major health risks in developing countries. Thrombin plays a central role in blood coagulation, which is a crucial process involved in thrombosis. Direct thrombin inhibitors (DTIs) such as argatroban, dabigatran, dabigatran etexilate, lepirudin, desirudin and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases. DTIs appear to overcome the disadvantages of indirect thrombin inhibitors such as unfractionated heparins (UFH). Although these DTIs show specific advantages over indirect inhibitors, they still present limitations, such as a narrow therapeutic window, and bleeding and anaphylaxis as side-effects. Novel anticoagulant drugs need thus to be developed to overcome these limitations. In the search for additional candidate agents with improved efficacy, safety and high bioavailability in oral administration, a high number of compounds has been identified, such as those derived from the tripeptide template D-Phe-Pro-Arg, aptamers and peptides isolated from blood-sucking animals. These candidates may prove the new agents of choice for the treatment of cardiovascular diseases.

New Frontiers in Druggability

“…Thrombin (T23) is predicted to be druggable both by Cheng et al 8 and by FTMap, and now has direct (i.e., not prodrug) oral inhibitors. 103,104 With 15 probe clusters, the penicillin binding protein (T22) is borderline druggable by FTMap, and ligand binding substantially strengthens the hot spot. This protein binds piperacillin, 105 an approved but not orally bioavailable drug (MW= 517.5 g/mol), with an IC 50 of 166 nM.…”

Investigation of Interactions between Thrombin and Ten Phenolic Compounds by Affinity Capillary Electrophoresis and Molecular Docking

“…Compared with heparins, DTIs do not require antithrombin as a cofactor and do not bind to plasma proteins; therefore, they produce a more predictable anticoagulant effect, and variability of patient response is low relative to other drug classes [ 9 ]. In reality, they still present limitations such as a narrow therapeutic window, and bleeding and anaphylaxis as side effects [ 10 ]. Therefore, alternative antithrombotic therapies are under extensive investigation, and many entities from natural products are being isolated and studied to counteract these side effects [ 11 ].…”

Complement System Inhibition Modulates the Pro-Inflammatory Effects of a Snake Venom Metalloproteinase

“…In 2002, Mollnes et al described an in vitro human whole blood model to study the role of the complement system in sepsis (14). The anticoagulant used in this model is lepirudin, a recombinant form of hirudin derived from leeches that acts on thrombin and does not affect complement system activity (15). This model allows for the analysis of the role of complement activation in the production of inflammatory cytokines and chemokines and in the expression of activation molecules by leukocytes (14, 16).…”