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https://www.readbyqxmd.com/read/28105277/design-and-synthesis-of-novel-meta-linked-phenylglycine-macrocyclic-fviia-inhibitors
#1
Jeremy M Richter, Daniel L Cheney, J Alex Bates, Anzhi Wei, Joseph M Luettgen, Alan R Rendina, Timothy M Harper, Rangaraj Narayanan, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28089408/the-various-assays-for-measuring-activity-states-of-factor-viia-in-plasma-and-therapeutic-products-diagnostic-value-and-analytical-usefulness-in-various-pathophysiological-states
#2
REVIEW
Jean Amiral, Claire Dunois, Cédric Amiral, Jerard Seghatchian
The key coagulation factor FVII, and its activated form FVIIa, present a major interest for their role at the initiation phase of blood coagulation, and because they can activate all blood coagulation cascade, through the extrinsic, but also the intrinsic pathway. Blood activation initiated through FVII is first presented, as it is understood nowadays. Measurement of FVII and FVIIa were of main interest for epidemiological studies, but FVIIa contribution to assay results was only deduced. The introduction of specific FVIIa assays, functional or immunoassays, allowed measuring directly FVIIa without any interference of non-activated FVII, or other coagulation factors or their activated forms...
December 29, 2016: Transfusion and Apheresis Science
https://www.readbyqxmd.com/read/28035745/one-amino-acid-in-mouse-factor-viia-defines-its-endothelial-protein-c-receptor-binding-and-modulates-its%C3%A2-epcr-dependent-hemostatic-activity-in-vivo
#3
G Pavani, S M Zintner, L Ivanciu, J C Small, K A Stafford, J H Szeto, P Margaritis
BACKGROUND: Human activated Factor VII (hFVIIa), used in hemophilia treatment, binds to the endothelial Protein C (PC) receptor (EPCR) with unclear hemostatic consequences. Interestingly, mice lack the Factor VIIa (FVIIa)-EPCR interaction. Therefore, to investigate the hemostatic consequences of this interaction in hemophilia, we previously engineered a mouse FVIIa (mFVIIa) molecule that bound mouse EPCR (mEPCR) using 3 substitutions from mouse Protein C (mPC, Leu4→Phe, Leu8→Met and Trp9→Arg)...
December 30, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28033108/tissue-factor-promotes-breast-cancer-stem-cell-activity-in-vitro
#4
Hudhaifah Shaker, Hannah Harrison, Robert Clarke, Goran Landberg, Nigel J Bundred, Henri H Versteeg, Cliona C Kirwan
Cancer stem cells (CSCs) are a subpopulation of cells that can self-renew and initiate tumours. The clotting-initiating protein Tissue Factor (TF) promotes metastasis and may be overexpressed in cancer cells with increased CSC activity. We sought to determine whether TF promotes breast CSC activity in vitro using human breast cancer cell lines. TF expression was compared in anoikis-resistant (CSC-enriched) and unselected cells. In cells sorted into of TF-expressing and TF-negative (FACS), and in cells transfected to knockdown TF (siRNA) and overexpress TF (cDNA), CSC activity was compared by (i) mammosphere forming efficiency (MFE) (ii) holoclone colony formation (Hc) and (iii) ALDH1 activity...
December 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27994741/discovery-of-phenylglycine-lactams-as-potent-neutral-factor-viia-inhibitors
#5
Nicholas R Wurtz, Brandon L Parkhurst, Wen Jiang, Indawati DeLucca, Xiaojun Zhang, Vladimir Ladziata, Daniel L Cheney, Jeffrey R Bozarth, Alan R Rendina, Anzhi Wei, Joseph M Luettgen, Yiming Wu, Pancras C Wong, Dietmar A Seiffert, Ruth R Wexler, E Scott Priestley
Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27899993/predictive-value-of-microparticle-associated-tissue-factor-activity-for-permeability-glycoprotein-mediated-multidrug-resistance-in-cancer
#6
Antonio Angelini, Sebastiano Miscia, Maria Antonietta Centurione, Roberta Di Pietro, Lucia Centurione
Multidrug resistance (MDR) protein 1, which is also known as permeability glycoprotein (Pgp), and tissue factor (TF) are recurrently overexpressed on the surface of cancer cells, likely in response to stimuli such as chemotherapy. Microparticles (MPs) released from cancer cells into the bloodstream express tumour markers on their surface that may be useful as predictive biomarkers for evaluating disease progression. The present study measured the level of TF/factor VII (FVII)-dependent coagulation of MPs isolated from the plasma of cancer patients with various tumours, who were undergoing chemotherapy...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27858671/effect-of-circulating-tissue-factor-on-hypercoagulability-in-type-2-diabetes-mellitus%C3%A2-studied-by-rheometry-and-dielectric%C3%A2-blood-coagulometry
#7
Isao Uchimura, Makoto Kaibara, Masayuki Nagasawa, Yoshihito Hayashi
BACKGROUND: Hypercoagulability in type 2 diabetes mellitus (T2DM) patients increases their risk of cardiovascular diseases. OBJECTIVE: The aim of this work was to investigate the hypercoagulation mechanism in T2DM patients in terms of circulating tissue factor (TF). METHODS: Whole blood coagulation tests by damped oscillation rheometry and dielectric blood coagulometry (DBCM) were performed. RESULTS: The average coagulation time was significantly shorter for T2DM patients than for healthy controls...
November 16, 2016: Biorheology
https://www.readbyqxmd.com/read/27646211/the-tipping-point-the-critical-role-of-therapeutic-apheresis-in-a-case-of-refractory-acquired-hemophilia
#8
Michael Losos, Scott Scrape, Sarita Joshi, Aaron Shmookler, Jian Chen
Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents...
September 20, 2016: Journal of Clinical Apheresis
https://www.readbyqxmd.com/read/27614059/ldl-receptor-related-protein-1-contributes-to-the-clearance-of-the-activated-factor-vii-antithrombin-complex
#9
J G Fazavana, V Muczynski, V Proulle, N Wohner, O D Christophe, P J Lenting, C V Denis
: Essentials Factor VIIa is cleared principally as a complex with antithrombin. Enzyme/serpin complexes are preferred ligands for the scavenger-receptor LRP1. Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1. Macrophage-expressed LRP1 contributes to the clearance of factor VIIa/antithrombin. SUMMARY: Background Recent findings point to activated factor VII (FVIIa) being cleared predominantly (± 65% of the injected protein) as part of a complex with the serpin antithrombin...
December 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27612545/synthesis-and-p1-sar-exploration-of-potent-macrocyclic-tissue-factor-factor-viia-inhibitors
#10
Vladimir Uladzimir Ladziata, Peter W Glunz, Yan Zou, Xiaojun Zhang, Wen Jiang, Swanee Jacutin-Porte, Daniel L Cheney, Anzhi Wei, Joseph M Luettgen, Timothy M Harper, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity...
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27592310/increased-circulating-procoagulant-and-anticoagulant-factors-as-tf-and-tfpi-according-to-severity-or-infecting-serotypes-in-human-dengue-infection
#11
Elzinandes Leal de Azeredo, Victor Edgar Fiestas Solórzano, Débora Batista de Oliveira, Cintia Ferreira Marinho, Luiz José de Souza, Rivaldo Venâncio da Cunha, Paulo Vieira Damasco, Claire Fernandes Kubelka, Luzia Maria de-Oliveira-Pinto
Tissue Factor (TF) is the initiator of coagulation and Tissue Factor Inhibitor (TFPI) is the physiological inhibitor of the TF/FVIIa complex. Circulating levels of TF and TFPI were quantified in dengue patients and the relationships with disease severity and infecting serotype analysed. A significant decrease in TF and TPFI plasma levels was observed in mild DF patients compared with severe dengue. Furthermore, both factors were associated with haemorrhagic manifestations. Finally, TF levels were significantly increased in DENV-1/2 infected patients as compared with DENV-4...
January 2017: Microbes and Infection
https://www.readbyqxmd.com/read/27522621/factor-viia-antithrombin-complex-a-possible-new-biomarker-for-activated-coagulation
#12
Luca Spiezia, Elena Campello, Fabio Dalla Valle, Barry Woodhams, Paolo Simioni
The activation of the extrinsic coagulation pathway occurs after endothelial injury when the tissue factor (TF), a transmembrane protein located outside the vasculature, binds factor VII (FVII) or activated FVII (FVIIa). Once formed, the TF-VIIa complex activates both factor IX and X and initiates the coagulation process. The TF-VIIa complex is inhibited by both TF pathway inhibitor (TFPI) and antithrombin (AT). The interaction between TF-VIIa and AT induces FVIIa-AT complex formation, which is released into the plasma...
August 15, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/27501279/trust-trial-bay-86-6150-use-in-haemophilia-with-inhibitors-and-assessment-for-immunogenicity
#13
J Mahlangu, P Paz, M Hardtke, F Aswad, J Schroeder
INTRODUCTION: The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. AIM: To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies...
November 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27480904/a-phase-iii-clinical-trial-of-a-mixture-agent-of-plasma-derived-factor-viia-and-factor-x-mc710-in-haemophilia-patients-with-inhibitors
#14
Y Shinkoda, A Shirahata, K Fukutake, J Takamatsu, M Shima, H Hanabusa, H Mugishima, H Takedani, K Kawasugi, M Taki, T Matsushita, A Tawa, K Nogami, S Higasa, Y Kosaka, T Fujii, M Sakai, M Migita, M Uchiba, K Kawakami, K Sameshima, Y Ohashi, H Saito
INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 μg kg(-1) MC710 (as FVIIa) once or twice (to a maximum of 180 μg kg(-1) ) over up to five bleeding episodes per subject...
August 1, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27455395/discovery-of-a-highly-potent-selective-and-orally-bioavailable-macrocyclic-inhibitor-of-blood-coagulation-factor-viia-tissue-factor-complex
#15
Xiaojun Zhang, Peter W Glunz, James A Johnson, Wen Jiang, Swanee Jacutin-Porte, Vladimir Ladziata, Yan Zou, Monique S Phillips, Nicholas R Wurtz, Brandon Parkhurst, Alan R Rendina, Timothy M Harper, Daniel L Cheney, Joseph M Luettgen, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing...
August 11, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27423005/tissue-factor-expressed-by-adherent-cells-contributes-to-hemodialysis-membrane-thrombogenicity
#16
Souad Lakbakbi, Alexandre Debrumetz, Christine Terryn, Jean Szymezak, Philippe Rieu, Philippe Nguyen
End-stage renal patients present a high risk of thrombosis and bleeding. Consequently, it is challenging to prevent clotting during hemodialysis. If a contact system induces thrombin generation in the extra corporeal circuit, recent data suggest a role of tissue factor (TF) in hemodialysis-associated thrombosis. Using a method of elution, we collected adhering cells to an acrylonitrile membrane layered by polythyleneimine (AN69-ST). Using optic microscopy and flow cytometry, we observed that adherent cells were mainly constituted by activated polymorphonuclear neutrophils (PMNs)...
August 2016: Thrombosis Research
https://www.readbyqxmd.com/read/27259465/the-unexpected-beneficial-role-of-smoking-in-preeclampsia
#17
REVIEW
Patrícia Nessralla Alpoim, Lara Carvalho Godoi, Melina de Barros Pinheiro, Letícia Gonçalves Freitas, Maria das Graças Carvalho, Luci Maria Dusse
We have recently investigated the association between the risk of developing PE and clinical, hemostatic, inflammatory and genetic parameters of 108 severe preeclamptic women. A multivariate logistic regression analysis was performed to assess what variables are independent risk factors for PE. Univariate analysis was performed including the variables in age, smoking condition, multiple pregnancy, blood group, phenotypes and alleles of IL-4, IL-5, IL-10, IL-6, IL-8, IL-12, IL-1β, IFN-γ, TNF-α, and the plasma levels of FVII, FVIIa, FVIIa-AT, FVIII, FVW, ADAMTS13, D-Di, PAI-1, ADMA...
August 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/27248165/a-plasma-proteolysis-pathway-comprising-blood-coagulation-proteases
#18
Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang
Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid β1-42 (Aβ1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes...
July 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27247997/protease-inhibitors-in-view-of-peptide-substrate-databases
#19
Birgit J Waldner, Julian E Fuchs, Michael Schauperl, Christian Kramer, Klaus R Liedl
Protease substrate profiling has nowadays almost become a routine task for experimentalists, and the knowledge on protease peptide substrates is easily accessible via the MEROPS database. We present a shape-based virtual screening workflow using vROCS that applies the information about the specificity of the proteases to find new small-molecule inhibitors. Peptide substrate sequences for three to four substrate positions of each substrate from the MEROPS database were used to build the training set. Two-dimensional substrate sequences were converted to three-dimensional conformations through mutation of a template peptide substrate...
June 27, 2016: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/27246245/cross-talk-between-the-tissue-factor-coagulation-factor-viia-complex-and-the-tyrosine-kinase-receptor-epha2-in-cancer
#20
Oskar Eriksson, Åsa Thulin, Anna Asplund, Geeta Hegde, Sanjay Navani, Agneta Siegbahn
BACKGROUND: Tissue Factor (TF) forms a proteolytically active complex together with coagulation factor VIIa (FVIIa) and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF/FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF/FVIIa and EphA2 using in vitro model systems and human cancer specimens. METHODS: Cleavage and phosphorylation of EphA2 was studied by Western blot...
2016: BMC Cancer
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