BIOCHEMICAL AND PHARMACOLOGICAL PROPERTIES OF SANORG-32701 - COMPARISON WITH THE SYNTHETIC PENTASACCHARIDE (SR-90107 ORG-31540) AND STANDARD HEPARIN

SANORG 32701 is a new sulfated pentasaccharide obtained by total chemi cal synthesis; It is an analogue of the ''synthetic pentasaccharide'' (SR 90107/ORG 31540), which represents the antithrombin III (AT-III) b inding site of heparin. Like SR 90107, it shows high affinity for huma n AT-III (k(d)=3.7+/-0.7 nmol/L) and is a potent catalyst of its inhib itory effect with regard to factor Xa (1100+/-31 versus 850+/-27 anti- Xa U/mg for SR 90107). SANORG 32701 inhibited thrombin generation occu rring via both the extrinsic and intrinsic pathways in vitro. After in travenous or subcutaneous administration to rabbits or rats, SANORG 32 701 displayed prolonged anti-factor Xa activity and inhibition of thro mbin generation ex vivo. SANORG 32701 was slowly eliminated, showing e limination half-lives between 2.8 and 4.9 hours with different doses. SANORG 32701 displayed antithrombotic activity by virtue of its potent iation of the antifactor 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) (ED(50) values were 25.5+/-4.1 and 91+/-12.7 nmol/kg, respectively). SANORG 32701 inhibited the accretion of fibrinogen I 125 to a preforme d thrombus in the rabbit jugular vein and significantly reduced thromb us 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 t hat 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 w ith standard heparin, SANORG 32701 (1000 nmol/kg IV) caused only minim al bleeding enhancement and exhibited a favorable antithrombotic activ ity/bleeding risk ratio, therefore showing that it might be considered as a promising compound in the treatment and prevention of various th rombotic diseases.