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

被引:165
作者
Herbert, JM
Hérault, JP
Bernat, A
van Amsterdam, RGM
Lormeau, JC
Petitou, M
van Boeckel, C
Hoffmann, P
Meuleman, DG
机构
[1] Sanofi Rech, Haemobiol Res Dept, F-31036 Toulouse, France
[2] NV Organon, NL-5340 BH Oss, Netherlands
关键词
D O I
10.1182/blood.V91.11.4197.411k09_4197_4205
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 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 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. (C) 1998 by The American Society of Hematology.
引用
收藏
页码:4197 / 4205
页数:9
相关论文
共 27 条
[1]   CONTRIBUTION OF 3-O-SULFATED AND 6-O-SULFATED GLUCOSAMINE RESIDUES IN THE HEPARIN-INDUCED CONFORMATIONAL CHANGE IN ANTITHROMBIN-III [J].
ATHA, DH ;
LORMEAU, JC ;
PETITOU, M ;
ROSENBERG, RD ;
CHOAY, J .
BIOCHEMISTRY, 1987, 26 (20) :6454-6461
[2]  
BEGUIN S, 1989, THROMB HAEMOSTASIS, V61, P397
[3]   EFFECTS OF HEPARIN, ITS LOW-MOLECULAR WEIGHT FRACTIONS AND OTHER GLYCOSAMINOGLYCANS ON THROMBUS GROWTH-INVIVO [J].
BONEU, B ;
BUCHANAN, MR ;
CADE, JF ;
VANRYN, J ;
FERNANDEZ, FF ;
OFOSU, FA ;
HIRSH, J .
THROMBOSIS RESEARCH, 1985, 40 (01) :81-89
[4]  
Boneu B, 1995, THROMB HAEMOSTASIS, V74, P1468
[5]  
BUCHANAN MR, 1985, BLOOD, V65, P198
[6]  
CADROY Y, 1993, THROMB HAEMOSTASIS, V70, P631
[7]   PHARMACOKINETIC AND ANTITHROMBOTIC PROPERTIES OF 2 PENTASACCHARIDES WITH HIGH-AFFINITY TO ANTITHROMBIN-III IN THE RABBIT - COMPARISON WITH CY216 [J].
CARRIE, D ;
CARANOBE, C ;
SAIVIN, S ;
HOUIN, G ;
PETITOU, M ;
LORMEAU, JC ;
VANBOECKEL, C ;
MEULEMAN, D ;
BONEU, B .
BLOOD, 1994, 84 (08) :2571-2577
[8]   STRUCTURE-ACTIVITY RELATIONSHIP IN HEPARIN - A SYNTHETIC PENTASACCHARIDE WITH HIGH-AFFINITY FOR ANTI-THROMBIN-III AND ELICITING HIGH ANTI-FACTOR-XA ACTIVITY [J].
CHOAY, J ;
PETITOU, M ;
LORMEAU, JC ;
SINAY, P ;
CASU, B ;
GATTI, G .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1983, 116 (02) :492-499
[9]   THROMBOLYSIS WITH HUMAN EXTRINSIC (TISSUE-TYPE) PLASMINOGEN-ACTIVATOR IN RABBITS WITH EXPERIMENTAL JUGULAR VEIN-THROMBOSIS - EFFECT OF MOLECULAR-FORM AND DOSE OF ACTIVATOR, AGE OF THE THROMBUS, AND ROUTE OF ADMINISTRATION [J].
COLLEN, D ;
STASSEN, JM ;
VERSTRAETE, M .
JOURNAL OF CLINICAL INVESTIGATION, 1983, 71 (02) :368-376
[10]   IMPORTANCE OF FACTOR-XA IN DETERMINING THE PROCOAGULANT ACTIVITY OF WHOLE-BLOOD CLOTS [J].
EISENBERG, PR ;
SIEGEL, JE ;
ABENDSCHEIN, DR ;
MILETICH, JP .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 91 (05) :1877-1883