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 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.
Herbert
J M
JM
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Hérault
J P
JP
Bernat
A
A
van Amsterdam
R G
RG
Vogel
G M
GM
Lormeau
J C
JC
Petitou
M
M
Meuleman
D G
DG
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D004558:Electric Stimulation; D065427:Factor Xa Inhibitors; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008026:Ligation; D008297:Male; D009844:Oligosaccharides / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin; D013927:Thrombosis / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014684:Venae Cavae
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009844:Oligosaccharides; C064764:PENTA; C101419:SANORG 32701; D005340:Fibrinogen; D006493:Heparin; D013925:Thromboplastin; D013917:Thrombin; D010959:Tissue Plasminogen Activator