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Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs

Fischer, Peter M.

Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs Thumbnail


Authors

Peter M. Fischer



Abstract

Vitamin K antagonists (VKA) have long been the default drugs for anticoagulant management in venous thrombosis. While efficacious, they are difficult to use due to interpatient dose–response variability and the risks of bleeding. The approval of fondaparinux, a heparin-derived factor Xa (fXa) inhibitor, provided validation for the development of direct oral anticoagulants (DOAC), and currently such inhibitors of thrombin and fXa are in clinical use. These agents can be used without regular coagulation monitoring, but the inherent risk of bleeding complications associated with blocking the common coagulation pathway remains. Efforts are now underway to develop DOACs that inhibit components of the intrinsic and extrinsic coagulation cascades upstream of thrombin and fX. Evidence from humans and from transgenic animal models suggests that this strategy may provide a better therapeutic margin between antithrombotic and antihemostatic effects. Here the design of active-site inhibitors of S1A proteases involved in coagulation and fibrinolysis is summarized.

Journal Article Type Article
Acceptance Date Oct 26, 2017
Online Publication Date Oct 26, 2017
Deposit Date Nov 10, 2017
Publicly Available Date Nov 10, 2017
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 61
Issue 9
DOI https://doi.org/10.1021/acs.jmedchem.7b00772
Public URL https://nottingham-repository.worktribe.com/output/889940
Publisher URL http://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00772

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