Chemical synthesis and pharmacological properties of heparin pentasaccharide analogues.

ID: ALA5154796

Journal: Eur J Med Chem

Title: Chemical synthesis and pharmacological properties of heparin pentasaccharide analogues.

Authors: Zhou Z, Zhang L, Wu X, Luo L, Wu J, Xu D, Wu M.

Abstract: 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+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 anti-factor 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 (t_1/2) were more than 2-fold of that of fondaparinux. These results suggested the pentasaccharide analogues may exhibit better pharmacokinetic and predictable pharmacodynamic characteristics.

CiteXplore: 35279609

DOI: 10.1016/j.ejmech.2022.114256

Patent ID: ┄