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Title: Design, synthesis and biological evaluation of novel FXIIIa inhibitors
Author: Avery, Craig Alex
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Thrombosis constitutes the most serious health issue in the developed world, causing more deaths than any other condition. Despite advances in therapy and a recent flurry of new drugs currently being tested in the clinic, the condition is increasing in prevalence largely due to the increasing age of the populations in the developed world. Current therapy relies on oral agents such as warfarin and aspirin, which both suffer from severe side effects. Additionally long term subcutaneous injection of FXa inhibitors is another useful therapy. There is thus an urgent need for fast acting, predictable and mild oral agents, which can be prescribed for the long term management of thrombosis. FXIII is the final enzyme involved in the blood coagulation cascade and has been shown to be crucial to the development of stabilised blood clots. Inhibition of this enzyme is an area that has been under-researched despite convincing evidence of the therapeutic potential of such an approach. This project has applied a structure based ligand design approach to attempt to identify novel inhibitors for FXIIIa. The search for new reversible agents led to the identification of the flavone Baicalein as a moderate inhibitor, which was identified from a vHTS approach using the eHiTs program, unfortunately this compound did not prove to be a synthetically tractable core. De novo design using the program SPROUT was also conducted producing a selection of target scaffolds, examples of which were synthesized and assayed against FXIII. This approach proved entirely unsuccessful in terms of producing molecules possessing enzymatic activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available