SR123781A, a synthetic heparin mimetic.
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.
Herbert
J M
JM
Cardiovascular/Thrombosis Research Department, Sanofi-Synthélabo, Toulouse, France. jean-marc.herbert@sanofi-synthelabo.com
Hérault
J P
JP
Bernat
A
A
Savi
P
P
Schaeffer
P
P
Driguez
P A
PA
Duchaussoy
P
P
Petitou
M
M
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000991:Antithrombins / Q000378:metabolism; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006801:Humans; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010215:Papio; D010974:Platelet Aggregation / Q000187:drug effects; D011134:Polysaccharides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D020246:Venous Thrombosis / Q000188:drug therapy
D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D011134:Polysaccharides; C446839:SR 123781A; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa