Dual anticoagulant/antiplatelet persulfated small molecules

Correia-da-Silva, Marta; Sousa, Emı́lia; Duarte, Bárbara; Marques, António; Cunha‐Ribeiro, L. M.; Pinto, Madalena

doi:10.1016/j.ejmech.2011.03.016

Cited by 41 publications

(37 citation statements)

References 40 publications

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“…The concentrations of 6 required to double PT and APTT were measured, as described earlier. 43–46 Figure 7 shows the variation in PT and APTT in the presence of varying concentrations of 6 . A 2-fold increase in PT required 298 µg/mL of 6 .…”

Section: Resultsmentioning

confidence: 99%

Sulfated Pentagalloylglucoside Is a Potent, Allosteric, and Selective Inhibitor of Factor XIa

et al. 2013

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Inhibition of factor XIa (FXIa) is a novel paradigm for developing anticoagulants without major bleeding consequences. We present the discovery of sulfated pentagalloylglucoside (6) as a highly selective inhibitor of human FXIa. Biochemical screening of a focused library led to the identification of 6, a sulfated aromatic mimetic of heparin. Inhibitor 6 displayed a potency of 551 nM against FXIa, which was at least 200-fold more selective than other relevant enzymes. It also prevented activation of factor IX and prolonged human plasma and whole blood clotting. Inhibitor 6 reduced VMAX of FXIa hydrolysis of chromogenic substrate without affecting the KM suggesting an allosteric mechanism. Competitive studies showed that 6 bound in the heparin-binding site of FXIa. No allosteric small molecule has been discovered to date that exhibits equivalent potency against FXIa. Inhibitor 6 is expected to open up a major route to allosteric FXIa anticoagulants with clinical relevance.

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Section: Resultsmentioning

confidence: 99%

Sulfated Pentagalloylglucoside Is a Potent, Allosteric, and Selective Inhibitor of Factor XIa

et al. 2013

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“…Fundamental research is necessary for scaffold hopping so as to derive clinically viable candidates. Yet, scaffold hopping is challenging as demonstrated by our earlier work 30–34 as well as by recent efforts from the Pinto group, 48,49 both of which indicate relatively weak affinity of the designed molecules.…”

Section: Conclusion and Significancementioning

confidence: 87%

Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

2011

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Antithrombin is a key regulator of coagulation and prime target of heparins, clinically used anticoagulants. Heparins induce a two-step conformational activation of antithrombin, a process that has remained challenging to target with molecules devoid of the antithrombin-binding pentasaccharide DEFGH. Computational screening of a focused library led to the design of two tetra-sulfated N-arylacyl tetrahydroisoquinoline variants as potential non-saccharide activators of antithrombin. A high yielding synthetic scheme based on Horner-Wadsworth-Emmons or Pictet-Spengler reactions was developed to facilitate the functionalization of the tetrahydoisoquinoline ring, which upon further amidation, deprotection, and sulfation gave the targeted non-saccharide activators. Spectrofluorometric measurement of affinity displayed antithrombin binding affinities in the low to high micromolar range at pH 6.0, I 0.05, 25 ºC. Measurement of second-order rate constants of antithrombin inhibition of factor Xa in the presence and absence of the designed activators showed antithrombin activation in the range of 8 – 80-fold in the pH 6.0 buffer. This work puts forward 20c, a novel tetra-sulfated N-arylacyl tetrahydroisoquinoline-based molecule, that activates AT only 3.8-fold less than that achieved with DEFGH suggesting a strong possibility of rationally designing sulfated organic molecules as clinically relevant AT activators.

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“…The study found that 3‐ O ‐rutinosides ( 46 and 47 ) directly inhibited FXa and 7‐ O ‐rutinosides ( 48 and 49 ) inhibited FXa via AT. Subsequently, trans ‐resveratrol 3‐β‐ d ‐glucopyranoside persulfate ( 50 ) was prepared as a dual anticoagulant/antiplatelet agent …”

Section: Heparin Mimeticsmentioning

confidence: 99%

Heparin mimetics with anticoagulant activity

Al-Nahain

Ignjatović

Monagle

et al. 2018

Medicinal Research Reviews

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Heparin, a sulfated polysaccharide belonging to the glycosaminoglycan family, has been widely used as an anticoagulant drug for decades and remains the most commonly used parenteral anticoagulant in adults and children. However, heparin has important clinical limitations and is derived from animal sources which pose significant safety and supply problems. The ever growing shortage of the raw material for heparin manufacturing may become a very significant issue in the future. These global limitations have prompted much research, especially following the recent well-publicized contamination scandal, into the development of alternative anticoagulants derived from non-animal and/or totally synthetic sources that mimic the structural features and properties of heparin. Such compounds, termed heparin mimetics, are also needed as anticoagulant materials for use in biomedical applications (e.g., stents, grafts, implants etc.). This review encompasses the development of heparin mimetics of various structural classes, including synthetic polymers and non-carbohydrate small molecules as well as sulfated oligo- and polysaccharides, and fondaparinux derivatives and conjugates, with a focus on developments in the past 10 years.

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Dual anticoagulant/antiplatelet persulfated small molecules

Cited by 41 publications

References 40 publications

Sulfated Pentagalloylglucoside Is a Potent, Allosteric, and Selective Inhibitor of Factor XIa

Sulfated Pentagalloylglucoside Is a Potent, Allosteric, and Selective Inhibitor of Factor XIa

Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

Heparin mimetics with anticoagulant activity

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