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Peptidomimetic thrombin inhbibitors
Kikelj, Danijel
The central position of thrombin in the coagulation cascade has made it a popular target for discovery of novel antithrombotic agents. Starting with hirudin, a natural peptide isolated from the ...medicinal leech, its shorter synthetic analogue hirulog, and argatroban, the first therapeutically used synthetic small-molecule thrombin active site inhibitor, hundreds of direct thrombin inhibitors have been discovered over the last 20 years. Most of them are peptidomimetic compounds, based on the amino acid sequence of fibrinogen which binds into the thrombin active site. Since elucidation of the crystal structure of human thrombin in 1989, the structure-based design of low-molecular-weight peptidomimetic thrombin inhibitors has been greatly aidedby the use of x-ray crystallographic analysis of thrombin- inhibitor complexes. The ultimate goal of most research programmes and drug optimizationstrategies is to develop an orally bioavailable, small-molecule, direct thrombin inhibitor that would be suitable for once or twice daily dosing. An overview of the most advanced peptidomimetic direct thrombin inhibitors bivalirudin, argatroban, ximelagatran and dabigatran is presented.
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