Rational Design of Anticoagulant Drugs Using Oligosaccharide Chemistry

Hadri, Ahmed El; Petitou, Maurice

doi:10.2533/chimia.2011.14

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…A biotin moiety has been linked to the EP42675 molecule, and this neutralizable form of EP42675 named EP217609 (biotinylated EP42675) showed superimposable pharmacokinetic and pharmacodynamic time-profiles to EP42675 in both animals [14] and humans [17]. Avidin (an egg-derived protein) is the specific antidote of EP217609, and it neutralizes its anticoagulant activity after binding with high affinity and specificity to its biotin moiety [14][15][16][17][18][19]. The pharmacokinetics and pharmacodynamics of EP42675 showed low variability between and within subjects, indicating that EP42675 has a predictable pharmacokinetic/ pharmacodynamic profile.…”

Section: Discussionmentioning

confidence: 99%

EP42675, a synthetic parenteral dual‐action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs

Guéret

Krezel²,

Fuseau³

et al. 2014

Journal of Thrombosis and Haemostasis

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Summary Background EP42675 is a first‐in‐class, synthetic, parenteral, anticoagulant combining in a single molecule a direct thrombin inhibitor and an indirect factor Xa(FXa) inhibitor. Objectives To investigate the safety, pharmacokinetics, and pharmacodynamics of EP42675 and its interaction with aspirin, clopidogrel, and unfractionated heparin (UFH). Subjects and Methods In study 1, healthy male subjects were administered intravenously single‐ascending doses (1–10 mg) of EP42675 or placebo. In study 2, healthy male subjects were administered intravenously a single dose of 5 mg EP42675 on day 1 followed by oral administration of aspirin (100 mg) and clopidogrel (75 mg) once daily from day 8 to 21. On day 15, a second dose of 5 mg EP42675 was administered, and subjects were then randomized to receive a single dose of UFH (30 or 60 IU kg−1) or placebo. Results and Conclusions Mild bleedings were the only drug‐related adverse events. EP42675 pharmacokinetics were dose‐proportional and characterized by a low clearance, a small volume of distribution, a long terminal half‐life. EP42675 pharmacodynamics were characterized by a long‐lasting, dose‐dependent increase in activated clotting time, ecarin clotting time, thrombin time, anti‐FXa activity, activated partial thromboplastin time, prothrombin time, and a decrease in endogenous thrombin potential, measured by a thrombin generation test. Dose‐dependent additive effects were seen with UFH on coagulation tests. EP42675 had no additive effect on the inhibition of platelet aggregation induced by aspirin and clopidogrel. These results warrant further clinical development of this new class of anticoagulant.

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Section: Discussionmentioning

confidence: 99%

EP42675, a synthetic parenteral dual‐action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs

Guéret

Krezel²,

Fuseau³

et al. 2014

Journal of Thrombosis and Haemostasis

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“…Hydroxamates are also known to act on recently discovered target Peptidyl deformylase (present only in parasite) for antimalarial therapy [91]. Glycosyl hydroxamates (113) were synthesized by the reaction of hydroxyl amine hydrochloride with glycosylated beta amino acids. Another series of glycosyl hydroxamates (114) was prepared where the sugar counterpart was derived from galactose and is present in pyranose form (Fig.…”

Section: Novel Anti Malarials: Hydroxamic Acid Derivatives Of Carbohymentioning

confidence: 99%

“…Various heparin mimicking oligosaccharides were prepared with an aim to replace the low molecular weight heparins and polydisperse heparin by structurally-defined anticoagulants without any unwanted side-effects [113].…”

Section: Heparin In Medicinal Chemistrymentioning

confidence: 99%

Spirocyclic Nucleosides in Medicinal Chemistry: An Overview

Soengas

Silva²

2012

MRMC

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Pyranosides with 2,3‐trans Carbamate Groups: Exocyclic or Endocyclic Cleavage Reaction?

Manabe

Ito

2014

The Chemical Record

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Pyranosides with 2,3-trans carbamate groups exhibit high 1,2-cis selectivity in glycosylation reactions. Using glycosyl donors with N-benzyl 2,3-trans carbamate groups, an anti-Helicobacter pylori oligosaccharide was synthesized in an efficient manner. Moreover, pyranosides with 2,3-trans carbamate groups readily undergo anomerization from the β to the α configuration under mild acidic conditions via endocyclic cleavage. Acyclic cations generated during the endocyclic cleavage reaction were captured using reduction and intramolecular Friedel-Crafts reaction. By exploiting this anomerization, multiply aligned 1,2-trans glycosyl bonds can be transformed to 1,2-cis glycosyl bonds in a single operation.

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Rational Design of Anticoagulant Drugs Using Oligosaccharide Chemistry

Cited by 4 publications

References 27 publications

EP42675, a synthetic parenteral dual‐action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs

EP42675, a synthetic parenteral dual‐action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs

Spirocyclic Nucleosides in Medicinal Chemistry: An Overview

Pyranosides with 2,3‐trans Carbamate Groups: Exocyclic or Endocyclic Cleavage Reaction?

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