Development of a novel class of potent and selective FIXa inhibitors

Zhang, Ting; André, Patrick; Bateman, Thomas J.; Chen, Yiheng; Desai, Kaushal; Ellsworth, Kenneth; Geissler, Wayne M.; Guo, Liangqin; Hruza, Alan; Jian, Tianying; Meng, Dongfang; Parker, Dann L.; Qian, Xiaoxia; Reichert, Paul; Sherer, Edward C.; Shi, Min; Smith, Cameron J.; Sonatore, Lisa M.; Tschirret-Guth, Richard A.; Nolting, Andrew; Orr, Robert K.; Campeau, Louis‐Charles; Araki, Kazuto; Nishimura, Teruyuki; Sakurada, Isao; Wood, Harold B.

doi:10.1016/j.bmcl.2015.04.057

Cited by 15 publications

(12 citation statements)

References 18 publications

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“…These structures were obtained from the RCSB Protein Data Bank (rcsb.org) [ 33 , 34 ]. The PDB ID of these structures are 5TNT [ 10 ], 5TNO [ 10 ], 5EGM [ 12 ], 4ZAE [ 11 ], 4Z0K [ 14 ], and 4YZU [ 14 ] for FIXa, and 2W26 [ 7 ], 2P16 [ 6 ], 3KL6 [ 8 ], 2PHB [ 9 ], 3M36 [ 35 ], and 2XBX [ 36 ] for FXa. They are listed in Table 4 .…”

Section: Methodsmentioning

confidence: 99%

“…Some of the FXa inhibitors are apixaban [ 6 ], rivaroxaban [ 7 ], letaxaban [ 8 ] and eribaxaban [ 9 ]. Even though these direct oral anticoagulants (DOAC) manage the risk of bleeding in a better way compared to warfarin and heparin, they are also not completely free from bleeding risk and hence these drugs should be prescribed with proper caution [ 10 , 11 , 12 ]. Therefore, the search for safer anticoagulants is still a challenging area of research.…”

Section: Introductionmentioning

confidence: 99%

“…Selective inhibition of FIXa that falls under the intrinsic pathway, which is right above FXa in the downstream coagulation propagation ( Figure S1 , shown in the Supplementary Materials ), is hypothesized and validated for improved bleeding related risk with similar efficacy compared to the FXa inhibitors. The basic tenet of this strategy is the selective regulation of the intrinsic pathway through selective therapeutic agents that would not be affecting the targets in the extrinsic pathway and the common pathway [ 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the selective inhibitor design for FIXa is very critical toward the management of the clinical condition. Many lead optimization programs and a number of experimental data also support the necessity of selective design FIXa inhibitors [ 10 , 11 , 12 , 13 , 14 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Kundu

2021

Molecules

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Blood coagulation is an essential physiological process for hemostasis; however, abnormal coagulation can lead to various potentially fatal disorders, generally known as thromboembolic disorders, which are a major cause of mortality in the modern world. Recently, the FDA has approved several anticoagulant drugs for Factor Xa (FXa) which work via the common pathway of the coagulation cascade. A main side effect of these drugs is the potential risk for bleeding in patients. Coagulation Factor IXa (FIXa) has recently emerged as the strategic target to ease these risks as it selectively regulates the intrinsic pathway. These aforementioned coagulation factors are highly similar in structure, functional architecture, and inhibitor binding mode. Therefore, it remains a challenge to design a selective inhibitor which may affect only FIXa. With the availability of a number of X-ray co-crystal structures of these two coagulation factors as protein–ligand complexes, structural alignment, molecular docking, and pharmacophore modeling were employed to derive the relevant criteria for selective inhibition of FIXa over FXa. In this study, six ligands (three potent, two selective, and one inactive) were selected for FIXa inhibition and six potent ligands (four FDA approved drugs) were considered for FXa. The pharmacophore hypotheses provide the distribution patterns for the principal interactions that take place in the binding site. None of the pharmacophoric patterns of the FXa inhibitors matched with any of the patterns of FIXa inhibitors. Based on pharmacophore analysis, a selectivity of a ligand for FIXa over FXa may be defined quantitatively as a docking score of lower than −8.0 kcal/mol in the FIXa-grids and higher than −7.5 kcal/mol in the FXa-grids.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Kundu

2021

Molecules

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“…Antithrombin (AT) is a glycoprotein and a serine protease inhibitor produced by the liver, which can inhibit various activated proteases associated with coagulation, including TF-VIIa complex [ 27 ], factor IXa [ 28 ], factor Xa [ 29 ], and thrombin by covalently binding to their serine residues. Moreover, together with heparins, AT plays a key role in the inhibition of serine protease by forming a thrombin-AT-heparin ternary complex with the presence of thrombin.…”

Section: Anticoagulant Mechanism Of Heparinsmentioning

confidence: 99%

Techniques for Detection of Clinical Used Heparins

Zhao

2021

International Journal of Analytical Chemistry

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Heparins and sulfated polysaccharides have been recognized as effective clinical anticoagulants for several decades. Heparins exhibit heterogeneity depending on the sources. Meanwhile, the adverse effect in the clinical uses and the adulteration of oversulfated chondroitin sulfate (OSCS) in heparins develop additional attention to analyze the purity of heparins. This review starts with the description of the classification, anticoagulant mechanism, clinical application of heparins and focuses on the existing methods of heparin analysis and detection including traditional detection methods, as well as new methods using fluorescence or gold nanomaterials as probes. The in-depth understanding of these techniques for the analysis of heparins will lay a foundation for the further development of novel methods for the detection of heparins.

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Minor structural changes, major functional impacts: posttranslational modifications and drug targets

Kim

2022

Arch. Pharm. Res.

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Development of a novel class of potent and selective FIXa inhibitors

Cited by 15 publications

References 18 publications

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Techniques for Detection of Clinical Used Heparins

Minor structural changes, major functional impacts: posttranslational modifications and drug targets

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