Specifically Designed Oligosaccharides

Pentasaccharides such as fondaparinux or the long-acting idraparinux (Herbert et al., 1998) have minimal, if any, undesirable interactions with blood and vessel components, but their anticoagulant activity is limited to AT-mediated factor Xa inhibition. Additional thrombin inhibitory properties might further improve the anticoagulant efficacy of heparin-related oligosaccharides. Unfortunately, as with heparin, lengthening the sulfated oligosaccharide chain increases nonspecific binding that could have undesirable effects, such as binding to PF4 and associated risk of HIT. Thus, Petitou and coworkers (1999) synthesized "heparin mimetics" that inhibited thrombin, but failed to bind other proteins, particularly PF4. The most promising structure is the hexadecasaccharide SR123781A, which is undergoing clinical evaluation (Herbert et al., 2001). It is obtained from glucose through a convergent synthesis and consists of an AT-binding pentasaccharide sequence linked to a thrombin-binding domain via a neutral methylated hexasaccharide "spacer." It specifically catalyzes the AT-mediated inhibition of factor Xa (IC50 = 77 ± 5 ng/mL, 297 ± 13U/mg) and thrombin (IC50 = 4.0 ± 0.5ng/mL, 150 ± 30 U/mg), without any effect on heparin cofactor II and without binding to PF4. Compared with UFH and LMWH in animal studies, SR123781A exhibited a highly favorable antithrombotic bleeding ratio. This compound did not activate platelets in the presence of plasma from HIT patients.

FIGURE 6 Chemical structure of the synthetically produced pentasaccharide, Org 32701 (MW = 1991 Da; DS = 2; 1150 anti-Xa U/mg), with a higher degree of sulfation (10 sulfate groups) than the natural antithrombin-binding site. Abbreviations: DS, degree of sulfation; MW, molecular weight.
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