First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action

Guéret, P.; Combe, S.; Krezel, C.; Fuseau, Eliane; Giersbergen, Paul L. M. van; Petitou, Maurice; Neuhart, Eric

doi:10.1007/s00228-016-2077-2

Cited by 7 publications

(5 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EP217609 is a parenteral antithrombotic compound, combining, in one molecule, an indirect anti‐factor Xa inhibitor and a direct thrombin active site inhibitor associated with a biotin moiety that can be neutralized by avidin (Olson et al , ). This molecule was recently evaluated in humans (Gueret et al , ). However, no data are currently available in a CPB model.…”

Section: Discussionmentioning

confidence: 99%

Inactivated antithombin as anticoagulant reversal in a rat model of cardiopulmonary bypass: a potent and potentially safer alternative to protamine

et al. 2018

View full text Add to dashboard Cite

Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB). As an alternative to protamine, a recombinant inactive antithrombin (riAT) was designed as an antidote to heparin and was previously shown to be as potent as protamine in-vitro. In the present study, riAT was assessed for its ability to neutralize heparin after CPB in a rat model. After 60 min of CPB under heparin, rats received 5 mg/kg protamine, 37.5 mg/kg riAT or phosphate buffered saline (PBS) as placebo. Residual anticoagulant activity was assessed using the activated partial thromboplastin time assay before, and 10-30 min after reversion. Haemodynamic monitoring was performed and plasma histamine concentration was also measured. In this model, riAT appeared to be as efficient as protamine in neutralizing heparin. Ten minutes after injection, riAT and protamine both decreased heparin activity, to 1.8 ± 1.3 and 4.5 ± 1.4 u/ml, respectively (23.1 ± 5.1 u/ml in placebo group). Furthermore, evolution of mean carotid arterial pressure, heart rate and plasma histamine levels was comparable in rats treated with PBS or riAT, while protamine exhibited haemodynamic side effects and increased histamine plasma concentration. Thus, riAT could represent an advantage over protamine in CPB because it efficiently reverses heparin activity without negative effects on haemodynamic parameters and plasma histamine level.

show abstract

Section: Discussionmentioning

confidence: 99%

Inactivated antithombin as anticoagulant reversal in a rat model of cardiopulmonary bypass: a potent and potentially safer alternative to protamine

et al. 2018

View full text Add to dashboard Cite

show abstract

“…As a result, the anticoagulant activity is greatly improved. Moreover, administration of avidin could trigger a rapid and irreversible neutralization of EP217609 in humans . Currently, EP217609 is under evaluation of phase II clinical trials …”

Section: Synthetic Carbohydrate‐based Vaccinesmentioning

confidence: 99%

“…Moreover,a dministration of avidin could trigger ar apid and irreversible neutralization of EP217609 in humans. [34][35][36] Currently,E P217609 is under evaluation of phaseIIclinicaltrials. [37] Although fondaparinuxa nd its derivatives exhibit strong anticoagulant activities, the industrial synthetic route for fondaparinux involves about 55 steps with 0.1 %o verall yield.…”

Section: Synthetic Heparin-related Therapeuticsmentioning

confidence: 99%

Synthetic Glycans and Glycomimetics: A Promising Alternative to Natural Polysaccharides

Zhang

2018

Chemistry A European J

View full text Add to dashboard Cite

A large quantity of polysaccharide-derived conjugate vaccines have been developed to combat various pathogenic infections. Another prominent polysaccharide, heparin, is listed as an essential drug by the World Health Organization (WHO) to treat thrombus. One of their common problems is that they all derive from natural polysaccharides. Specifically, capsular polysaccharides are mainly obtained from bacterial fermentation and unfractionated heparin is extracted from animal tissues such as porcine mucosa. The quality of natural polysaccharides is inconsistent and traces of contamination would cause a disaster. By contrast, the use of chemical or chemoenzymatic methods could provide structurally homogeneous and quality-controlled glycans. To date, large numbers of polysaccharide fragments and their analogues have been synthesized and evaluated. Some of them even showed comparable activities to their corresponding natural polysaccharides. Here, the latest advances in these synthetic glycan analogues ranging from carbohydrate-based vaccines, heparin-related therapeutics and glycomimetics of polysaccharides are summarized.

show abstract

“…1,6-Di-O-acetyl-2,3,4-tri-O-methyl-α/β-D-glucopyranose (12). A solution of methyl α-D-glucopyranoside (5.00 g, 25.75 mmol) and TrCl (8.60 g, 30.85 mmol) in pyridine (30 mL) was stirred at 60 °C for 8 h. Subsequently the mixture was concentrated in vacuo and coevaporated with toluene twice.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Usually, the strategy used for the synthesis of idraparinux and related analogue (Idrabiotaparinux or EP217609 12 ) consists of assembling the G unit to H and then addition to the DEF trisaccharide (2) obtained by a sequence of glycosylation D + E + F. The GH fragment contains an unusual monosaccharide, L-(−)-iduronic acid, which is not available in nature as a simple monosaccharide. Preparation of the L-(−)-idopyranose building block is well-known and frequently starts from cheap D-(+)-glucose.…”

Section: ■ Introductionmentioning

confidence: 99%

Application of the EF and GH Fragments to the Synthesis of Idraparinux

2017

View full text Add to dashboard Cite

A novel total synthesis of fully protected idraparinux has been achieved. A short and efficient protocol for the synthesis of the EF fragment of idraparinux and its C5'-epi analogue (GH unit) has been developed. The same cellobiose unit was transformed in 14 steps into the fully protected EF and GH disaccharide fragments. The key step of this approach is an epimerization of C5 by an elimination-addition sequence leading to l-ido disaccharide (GH unit) with a total yield of 24% (36% for the EF fragment). 1,6-Anhydro ring opening gave suitable substrates for efficient synthesis of fully protected idraparinux. The fully protected antithrombotic pentasaccharide idraparinux was synthesized in 23 steps for the longest linear route, with a 1.7% overall yield from d-cellobiose and d-glucose.

show abstract

First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action

Cited by 7 publications

References 14 publications

Inactivated antithombin as anticoagulant reversal in a rat model of cardiopulmonary bypass: a potent and potentially safer alternative to protamine

Inactivated antithombin as anticoagulant reversal in a rat model of cardiopulmonary bypass: a potent and potentially safer alternative to protamine

Synthetic Glycans and Glycomimetics: A Promising Alternative to Natural Polysaccharides

Application of the EF and GH Fragments to the Synthesis of Idraparinux

Contact Info

Product

Resources

About