BIOCHEMICAL AND PHARMACOLOGICAL PROPERTIES OF SANORG-34006, A POTENT AND LONG-ACTING SYNTHETIC PENTASACCHARIDE

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical sy nthesis. It is an analog of the ''synthetic pentasaccharide'' (SR 9010 7/ORG 31540) which represents the antithrombin (AT) binding site of he parin. 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 a nd selective catalyst of the inhibitory effect of AT on factor Xa (1,2 40 +/- 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 intrave nous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti-factor Xa activity and inhibition of th rombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated aft er IV or SC administration to rats, rabbits, and baboons, showed excep tionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 d isplayed antithrombotic activity by virtue of its potentiation of the anti-factor Xa activity of AT. It strongly inhibited thrombus formatio n in experimental models of thromboplastin/stasis-induced venous throm bosis in rats (IV) and rabbits (SC) (ED50 values = 40.0 +/- 3.4 and 10 5.0 +/- 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti-factor Xa activity. SANOR G 34006 enhanced rt-PA-induced thrombolysis and inhibited accretion of I-125-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 ac cretion onto the thrombus under lysis. Contrary to standard heparin, S ANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species a nd, therefore, exhibited a favorable therapeutic index. We suggest tha t SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases. (C) 1998 by The American Society of H ematology.