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Biochemical and Pharmacological Properties of SANORG 34006, a
Potent and Long-Acting Synthetic Pentasaccharide
J.M. Herbert,
J.P. Hérault,
A. Bernat,
R.G.M. van Amsterdam,
J.C. Lormeau,
M. Petitou,
C. van Boeckel,
P. Hoffmann, and
D.G. Meuleman
From the Haemobiology Research Department, Sanofi Recherche,
Toulouse, France; and NV Organon, Oss, The Netherlands.
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.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4197-4205
© 1998 by The American Society of Hematology.
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