Design and synthesis of small molecule inhibitors of coagulation FXIIaTools Chen, Xi (2018) Design and synthesis of small molecule inhibitors of coagulation FXIIa. PhD thesis, University of Nottingham.
AbstractBlood coagulation factors, factor XII (FXII), plasma kallikrein (PK), factor XI (FXI), and high-molecular-weight kininogen (HMWK), are four proteins that are involved in the plasma contact activation system (CAS) and kallikrein-kinin system (KKS). FXII is the initiation point of the intrinsic pathway of blood coagulation and is also the link between procoagulant and proinflammatory reactions. A number of inhibitors for blood coagulation factors have been approved for clinical usage. These inhibitors not only show inhibitory activities against thrombosis, but also disrupt haemostasis causing excessive bleeding. Contrasted with other coagulation proteases, the deficiency in FXII, instead of causing excessive bleeding, only reduces thrombus formation in blood coagulation. This unique property has made FXII a potential target for the treatments of thrombosis. FXII inhibitors such as aptamers, antibodies and peptides have been reported. Due to their limitations, some inhibitors have poor selectivity or weak binding affinity. Some inhibitors (biopolymers) have pharmaceutical problems. A chemically synthesised FXII inhibitor, with high selectivity is of great importance. The current lack of small molecule FXII inhibitors is limiting efforts to fully understand and validate FXII as a drug target. This project aims to design and synthesise a novel class of 1, 2, 5-tri-substituted benzene urea compounds as potent FXIIa inhibitors.
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