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SR123781A, a synthetic heparin mimetic.

Abstract
SR123781A, a synthetic hexadecasaccharide comprising an antithrombin (AT) binding domain, a thrombin binding domain, and a neutral methylated hexasaccharide sequence, was obtained from glucose through a convergent synthesis. SR123781A showed high affinity for human AT (Kd = 58 +/- 22 nM) and was a potent catalyst of its inhibitory effect with regard to factor Xa (IC50) = 77 +/- 5 ng/ml - 297 +/- 13 U/mg) and thrombin (IC50 = 4.0 +/- 0.5 ng/ml - 150 +/- 30 U/mg). SR123781A which acted exclusively via AT (no effect via heparin cofactor II at a concentration of 6 microg/ml) inhibited thrombin generation occurring via both the extrinsic and intrinsic pathways in vitro in human plasma. SR123781A did not compete for 3H-heparin binding to PF4 and did not activate platelets in the presence of plasma from patients with heparin-induced thrombocytopenia. After intravenous or subcutaneous administration to rats, rabbits or baboons, SR123781A displayed prolonged anti-factor Xa and anti-factor IIa activity ex vivo. After intravenous injection to baboons, decreases of the anti-factor Xa and anti-thrombin activities were parallel and disappeared with the same pharmacodynamics. Intravenous administrations of SR123781A strongly inhibited thrombus formation in an experimental model of thromboplastin-induced venous thrombosis in rats with an ED50 value of 18 +/- 0.1 microg/kg (vs 77 +/- 3 microg/kg for heparin). SR123781A inhibited arterial thrombus formation induced on a silk thread in an arterio-venous shunt and in the vena cava (ED50 values of 225 +/- 10 and 27 +/- 8 microg/kg, respectively). Compared to standard and low molecular weight heparin and to presently used drugs, SR123781A exhibited a highly favourable antithrombotic/bleeding ratio therefore showing that it might be considered as a promising compound in the treatment and prevention of various thrombotic diseases.
AuthorsJ M Herbert, J P Hérault, A Bernat, P Savi, P Schaeffer, P A Driguez, P Duchaussoy, M Petitou
JournalThrombosis and haemostasis (Thromb Haemost) Vol. 85 Issue 5 Pg. 852-60 (May 2001) ISSN: 0340-6245 [Print] Germany
PMID11372679 (Publication Type: Journal Article)
Chemical References
  • Anticoagulants
  • Antithrombins
  • Factor Xa Inhibitors
  • Polysaccharides
  • SR 123781A
  • Heparin
  • Thrombin
  • Factor Xa
Topics
  • Animals
  • Anticoagulants (administration & dosage, chemical synthesis, pharmacokinetics)
  • Antithrombins (metabolism)
  • Binding Sites
  • Carbohydrate Conformation
  • Carbohydrate Sequence
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Factor Xa (metabolism)
  • Factor Xa Inhibitors
  • Heparin (administration & dosage, chemical synthesis, pharmacokinetics)
  • Humans
  • Molecular Mimicry
  • Molecular Sequence Data
  • Papio
  • Platelet Aggregation (drug effects)
  • Polysaccharides (administration & dosage, chemical synthesis, pharmacokinetics)
  • Rabbits
  • Rats
  • Thrombin (antagonists & inhibitors, metabolism)
  • Venous Thrombosis (drug therapy)

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