Structure Based Drug Design: Development of Potent and Selective Factor IXa (FIXa) Inhibitors

Wang, Shouming; Beck, Richard; Burd, Andrew; Blench, Toby J.; Marlin, Frédéric; Ayele, Tenagne; Buxton, Stuart; Dagostin, Claudio; Malic, Maja; Joshi, Rina; Barry, John; Sajad, Mohammed; Cheung, C. K.; Shaikh, Shaheda; Chahwala, Suresh B.; Chander, C. L.; Baumgartner, Christine; Holthoff, Hans‐Peter; Murray, E. J.; Blackney, M.; Giddings, Amanda

doi:10.1021/jm901476x

Cited by 28 publications

(20 citation statements)

References 11 publications

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“…In addition, our docking results indicate that there is a change of ligand binding vector probably due to the repulsive force between the additional fluoro substituent and electron-rich−OH of Ser195, which also might be one of the reasons for the slight loss of activity. This, to some degree, is in agreement with the conclusion suggested by Wang et al 12 .…”

Section: Comfa Contoursupporting

confidence: 94%

“…Consequently, at the initiation stage of the cascade, the upstream inhibition of FIXa would represent a wonderful method for the development of anticoagulants with good selectivity and safety. Recently, several classes of compounds, such as 5-amidinoindoles 1 , pyrazole analogues 8,9 , 5-amidinobenzo[b]thiophenes 10 , benzothiophenes 11,12 and so on, have been reported as FIXa inhibitors. Among them, the benzothiophenes, designed on the basis of FIXa X-ray crystallography, illustrate high potential and selectivity for FIXa.…”

Section: Research Articlementioning

confidence: 99%

“…A diverse dataset of 84 benzothiophene analogues with the experimental values for the K i of the FIXa inhibitors were taken from literatures 11,12 that are published by the same research group. The activity of all the molecules was measured by the same assay on a recombinant form of human factor IX, which was prepared to overcome potential problems with the use of ethylene glycol in a factor IXa inhibition assay 11 .…”

Section: Datasetmentioning

confidence: 99%

“…The crystal structure of IZX with human FIXa shows some characteristics of the binding pocket 12 divided into four parts as shown in Figure 2. The pocket sandwiches the inhibitor between Gln192, Cys191, Ser190, Asp189 on the left and Trp215, Gly216, Phe174 on the right.…”

Section: Molecular Dockingmentioning

confidence: 99%

See 3 more Smart Citations

Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies

Ming

Zhang

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Comfa Contoursupporting

confidence: 94%

Section: Research Articlementioning

confidence: 99%

Section: Datasetmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

See 2 more Smart Citations

Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies

Ming

Zhang

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The amidine group contributing the positive ionizable characteristic feature which is responsible for interaction with acidic amino acid like ASP. [44][45][46] Oral FIXa inhibitors TTP889 was the proprietary oral FIXa inhibitor manufactured by Transtech Pharma Winston Salem, North Carolina US. The inhibition was investigated by the FIXIT study.…”

Section: Modifications Atmentioning

confidence: 99%

Factor VIIa and Factor IXa Inhibitors as Anticoagulants: A Review

Sahadeo¹,

Balkrishna²,

Suresh³

et al. 2017

IJPER

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Introduction: Anticoagulants are used as preventive agents in deep vein thrombosis to prevent blood clots, venous and arterial thromboembolism, but the current therapy of anticoagulants have several limitations like patient variable response, enhanced chances of bleeding and heparin-induced thrombocytopenia (HIT). Factor VIIa and factor IXa play an important role in coagulation cascade and hence are promising targets for drug development. FIXa has been targeted by various means including oral inhibitors (TTP889), monoclonal antibodies (SB249417) and RNA aptamers which have passed various phases of clinical trials. Objectives: Though advances in development of inhibitors of FVIIa/TF and FIXa have reached various phases of clinical trials none of the clinical trial candidates have reached the market. Methodology: This review summarizes available information on FVIIa/TF and FIXa, their active site, crystallographic structure, available inhibitors, earlyphase clinical trial study and also the recent efforts in the discovery of FVIIa/TF and FIXa inhibitors. Summary: Despite the fact that more complexity is observed in designing of anticoagulant as FVIIa/TF complex and FIXa inhibitors, these will remain an important and validated target for the design and development of anticoagulants.

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Anticoagulants

Quan

Glunz

Luettgen

2021

Burger's Medicinal Chemistry and Drug Discovery

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Although blood circulation is highly regulated, dysfunctional activities resulting from either deficient or excessive coagulation have serious health consequences. Insufficient clotting can lead to prolonged bleeding and hemophilia‐related conditions. Over activation of coagulation can lead to thrombosis‐related disorders, such as deep venous thrombosis, pulmonary embolism, and stroke, which together are a major cause of morbidity and mortality. Studies of the biological pathways leading to coagulation, and the resultant development and refinement of the coagulation cascade, have identified many potential biological targets for therapeutic intervention. The major challenge regarding the treatment and prevention of thromboembolic diseases is the requirement for effective anticoagulant therapy without exposing patients to an increased risk of bleeding. Preclinical and clinical evaluations of anticoagulant agents highlight this efficacy/bleeding dichotomy. This article presents the medicinal chemistry efforts leading to the discovery of inhibitors of the coagulation cascade, resulting in marketed thrombin and Factor Xa inhibitors. Also reported is the progress toward identifying emerging anticoagulants.

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Structure Based Drug Design: Development of Potent and Selective Factor IXa (FIXa) Inhibitors

Cited by 28 publications

References 11 publications

Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies

Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies

Factor VIIa and Factor IXa Inhibitors as Anticoagulants: A Review

Anticoagulants

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