Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs
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) inhibi...
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| Format: | Article |
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American Chemical Society
2017
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| Online Access: | https://eprints.nottingham.ac.uk/48039/ |
| _version_ | 1848797677925433344 |
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| author | Fischer, Peter M. |
| author_facet | Fischer, Peter M. |
| author_sort | Fischer, Peter M. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:07:41Z |
| format | Article |
| id | nottingham-48039 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:07:41Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-480392020-05-04T19:14:19Z https://eprints.nottingham.ac.uk/48039/ Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs Fischer, Peter M. 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. American Chemical Society 2017-10-26 Article PeerReviewed Fischer, Peter M. (2017) Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs. Journal of Medicinal Chemistry, 61 (9). pp. 3799-3822. ISSN 1520-4804 http://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00772 doi:10.1021/acs.jmedchem.7b00772 doi:10.1021/acs.jmedchem.7b00772 |
| spellingShingle | Fischer, Peter M. Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs |
| title | Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs |
| title_full | Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs |
| title_fullStr | Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs |
| title_full_unstemmed | Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs |
| title_short | Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs |
| title_sort | design of small-molecule active-site inhibitors of the s1a family proteases as procoagulant and anticoagulant drugs |
| url | https://eprints.nottingham.ac.uk/48039/ https://eprints.nottingham.ac.uk/48039/ https://eprints.nottingham.ac.uk/48039/ |