Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide.

Abstract

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the "synthetic pentasaccharide" (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 +/- 0.3 v 48 +/- 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 +/- 15 anti-factor Xa U/mg v 850 +/- 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 105.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANORG 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of 125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

• Authors: J M Herbert, J P Hérault, A Bernat, R G van Amsterdam, J C Lormeau, M Petitou, C van Boeckel, P Hoffmann, D G Meuleman
• Journal: Blood (Blood) Vol. 91 Issue 11 Pg. 4197-205 (Jun 01 1998) ISSN: 0006-4971 [Print] United States
• PMID: 9596667 (Publication Type: Journal Article)

Chemical References

• Factor Xa Inhibitors
• Fibrinolytic Agents
• Oligosaccharides
• PENTA
• idraparinux
• Thromboplastin
• Thrombin

Topics

• Animals
• Carbohydrate Sequence
• Dose-Response Relationship, Drug
• Factor Xa Inhibitors
• Fibrinolytic Agents (administration & dosage, chemistry, pharmacology)
• Humans
• Molecular Sequence Data
• Oligosaccharides (chemistry, pharmacology)
• Papio
• Partial Thromboplastin Time
• Rabbits
• Rats
• Thrombin (metabolism)
• Thromboplastin
• Thrombosis (prevention & control)