Recent advances in the discovery and development of factor XI/XIa inhibitors

Al‐Horani, Rami A.; Afosah, Daniel K.

doi:10.1002/med.21503

Cited by 65 publications

(97 citation statements)

References 187 publications

(444 reference statements)

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“…Likewise, the PT assay evaluates the effect of molecules on the extrinsic pathway of coagulation involving FVIIa, in addition to the effect on the common pathway. The TT screens the effect on the formation of fibrin from fibrinogen after the addition of known amounts of thrombin to the plasma sample [21]. The concentrations of pentamidine required to double APTT, PT, and TT were measured, as described earlier [8,9].…”

Section: Resultsmentioning

confidence: 99%

The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

2019

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Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine’s effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC50) value of ~3.6 μM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC50 values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin.

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Section: Resultsmentioning

confidence: 99%

The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

2019

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“…Along these lines, direct FXa inhibitors are therapeutically approved for the prevention and/or treatment of venous thromboembolism, including deep vein thrombosis and pulmonary embolism [45,46]. Mechanistically, the four approved drugs in Fig.…”

Section: Direct Factor Xa Inhibitorsmentioning

confidence: 99%

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Al‐Horani

2020

Am J Cardiovasc Drugs

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Human factor Xa (FXa) is a serine protease of the common coagulation pathway. FXa is known to activate prothrombin to thrombin, which eventually leads to the formation of cross-linked blood clots. While this process is important in maintaining hemostasis, excessive thrombin generation results in a host of thrombotic conditions. FXa has also been linked to inflammation via protease-activated receptors. Together, coagulopathy and inflammation have been implicated in the pathogenesis of viral infections, including the current coronavirus pandemic. Direct FXa inhibitors have been shown to possess anti-inflammatory and antiviral effects, in addition to their established anticoagulant activity. This review summarizes the pharmacological activities of direct FXa inhibitors, their pharmacokinetics, potential drug-drug interactions and adverse effects, and the details of clinical trials involving direct FXa inhibitors in coronavirus disease 2019 (COVID-19) patients. Key Points Factor Xa is a serine protease in the common coagulation pathway, the excessive stimulation of which leads to a host of thrombotic conditions. Factor Xa has also been linked to inflammation as well as viral infections. In addition to their established anticoagulant properties, factor Xa inhibitors have exhibited significant anti-inflammatory and antiviral effects in several testing settings. Currently, there are > 10 clinical trials for evaluating the potential of factor Xa inhibitors in coronavirus disease 2019 (COVID-19) patients. Strategies to administer these drugs parenterally may facilitate their use in critically ill COVID-19 patients.

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“…Preclinical studies based on other natural or synthetic direct FXa inhibitors have been completed with promising results, 63,64 thus paving the way to planning randomized clinical trials for testing their efficacy and safety profiles in vivo. Notably, although most of these new compounds act as direct FXa inhibitors, encouraging evidence is also emerging on some antithrombotic molecules and aptamers targeting intrinsic pathway factors (i.e., FIXa, FXIa, and FXIIa), as recently reviewed elsewhere, [65][66][67] while no additional direct thrombin inhibitors seem to be in the pipeline of the pharmacological industry to the best of our knowledge. Some explanation can be proposed, including the hypothesis that the inhibition of FXa, which is in an upstream position in the coagulation cascade, may not directly interfere with preexisting thrombin activity, thus enabling a more effective balance between the risk of bleeding and thrombosis.…”

Section: Resultsmentioning

confidence: 99%

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

Lippi

Gosselin

Favaloro

2019

Semin Thromb Hemost

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Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59–7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

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Recent advances in the discovery and development of factor XI/XIa inhibitors

Cited by 65 publications

References 187 publications

The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

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