Chemical synthesis and pharmacological properties of heparin pentasaccharide analogues

The pentasaccharide fondaparinux is a synthetic anticoagulant based on heparin antithrombin-binding sequence. Fondaparinux improves safety and predictable pharmacodynamics compared with heparins; however, it requires a complicate synthesis process which contain more than 50 steps of synthesis. Herein, we designed and synthesized four fondaparinux analogues (compounds 1, 2, 3, 4) using a [2 thorn 3] convergent synthetic method, which greatly simplified the synthetic process, improved the product yield, and curtailed the expenditures. These synthesized compounds showed stronger anticoagulant activities by factor Xa inhibition (IC50 725-1126 nM vs. 1909 nM for fondaparinux) in the AT-dependent manner. After subcutaneous (s.c.) administration to rats, the compounds displayed long-lasting antifactor Xa activities and inhibition of thrombin generation ex vivo. Compared with fondaparinux, these compounds were slowly eliminated after s.c. administration to rats, the half-lies (t1/2) were more than 2fold of that of fondaparinux. These results suggested the pentasaccharide analogues may exhibit better pharmacokinetic and predictable pharmacodynamic characteristics. (c) 2022 Elsevier Masson SAS. All rights reserved.