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.