PubMed · 8044114
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F Taylor, M Ramsay, A Renton, H Cohen. 1994-07-16. Guidelines for anticoagulation.. https://doi.org/10.1136/bmj.309.6948.197
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A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-L-Arg-alpha-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multi-step synthesis affords the desired alpha-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of the tissue factor (TF) VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10e bound to the TF/VIIa complex was obtained that explains the observed selectivity. The alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue factor VIIa, with some analogues demonstrating selectivity versus thrombin.
The recently released PREVENT trial provides some answers.
Heparin and the vitamin K antagonist warfarin have been in clinical use for more than 50 years. However, both are associated with several well-documented drawbacks that limit their use. Warfarin can be administered orally, making it the agent of choice for long-term management of thromboembolic conditions, but frequent coagulation monitoring is necessary because of its unpredictable anticoagulant effect--the result, in part, of food and drug interactions-and its narrow therapeutic window. Heparin and low-molecular-weight heparin (LMWH) can be administered parenterally only. Coagulation monitoring is also required with heparin although not with LMWH, due to reduced levels of plasma protein binding. In the last 10 years, in the quest to develop new agents that are at least as effective as those currently available, with improved safety and greater ease of use, anticoagulants that target almost every step in the coagulation pathway have been developed. These include inhibitors of the factor VIIa (FVIIa)/tissue factor complex, FIXa inhibitors, direct and antithrombin-dependent FXa inhibitors, agents that enhance the protein C anticoagulant pathway, and direct thrombin inhibitors (DTIs) that inhibit the activity of thrombin. Of the new agents, three DTIs-hirudin, bivalirudin, and argatroban-and the synthetic pentasaccharide (Arixtra) are approved for clinical use. Three other new agents-activated protein C (APC), tissue factor pathway inhibitor (TFPI), and the oral DTI ximelagatran (Exanta, AstraZeneca)-have been evaluated in Phase III studies. The mechanism of action and properties of these new anticoagulants and their potential to replace those in current use will be reviewed here.