SANORG 32701 is a new sulfated pentasaccharide obtained by total chemical synthesis. It is analogue of the "synthetic pentasaccharide" (
SR 90107/
ORG 31540), which represents the
antithrombin III (AT-III) binding site of
heparin. Like
SR 90107, it shows high affinity for human AT-III (Kd = 3.7 +/- 0.7 nmol/L) and is a potent catalyst of its inhibitory effect with regard to
factor Xa (1100 +/- 31 versus 850 +/- 27 anti-Xa U/mg for
SR 90107).
SANORG 32701 inhibited
thrombin generation occurring via both the extrinsic and intrinsic pathways in vitro. After intravenous or subcutaneous administration to rabbits or rats,
SANORG 32701 displayed prolonged anti-
factor Xa activity and inhibition of
thrombin generation ex vivo.
SANORG 32701 was slowly eliminated, showing elimination half-lives between 2.8 and 4.9 hours with different doses.
SANORG 32701 displayed antithrombotic activity by virtue of its potentiation of the anti-
factor Xa activity of AT-III. It strongly inhibited
thrombus formation in an experimental model of
thromboplastin-induced
venous thrombosis in rats (intravenously) and rabbits (subcutaneously) (ED50 values were 25.5 +/- 4.1 and 91 +/- 12.7 nmol/kg, respectively).
SANORG 32701 inhibited the accretion of
fibrinogen I 125 to a preformed
thrombus in the rabbit jugular vein and significantly reduced
thrombus growth occurring after electrical stimulation of the rabbit carotid artery. In the rabbit,
intravenous injection of
SANORG 32701 enhanced
tissue plasminogen activator (TPA)-induced thrombolysis, suggesting that concomitant use of
SANORG 32701 during TPA
therapy may be helpful in preventing
thrombus accretion, thus facilitating clot lysis. In the rat,
SANORG 32701 potently inhibited
thrombus formation induced on a
silk thread in an arteriovenous shunt and in the vena cava. Compared with standard
heparin,
SANORG 32701 (1000 nmol/kg IV) caused only minimal
bleeding enhancement and exhibited a favorable antithrombotic activity/
bleeding risk ratio, therefore showing that it might be considered as a promising compound in the treatment and prevention of various thrombotic diseases.