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Phosphinanes and Azaphosphinanes as Potent and Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Apr 08; Vol. 64 (7), pp. 3897-3910. Date of Electronic Publication: 2021 Mar 25. - Publication Year :
- 2021
-
Abstract
- Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure-activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.
- Subjects :
- Animals
Aza Compounds chemical synthesis
Aza Compounds metabolism
Carboxypeptidase B2 metabolism
Catalytic Domain
Cyclic P-Oxides chemical synthesis
Cyclic P-Oxides metabolism
Fibrinolysis drug effects
Fibrinolytic Agents chemical synthesis
Fibrinolytic Agents metabolism
Humans
Male
Molecular Docking Simulation
Molecular Structure
Phosphinic Acids chemical synthesis
Phosphinic Acids metabolism
Protease Inhibitors chemical synthesis
Protease Inhibitors metabolism
Protein Binding
Rats, Sprague-Dawley
Structure-Activity Relationship
Rats
Aza Compounds pharmacology
Carboxypeptidase B2 antagonists & inhibitors
Cyclic P-Oxides pharmacology
Fibrinolytic Agents pharmacology
Phosphinic Acids pharmacology
Protease Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33764059
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c02072