Synthesis and pharmacological properties of a close analogue of an antithrombotic pentasaccharide (SR 90107A/ORG 31540)

Journal of Medicinal Chemistry
M PetitouJ M Herbert

Abstract

The synthetic pentasaccharide (1) corresponding to the heparin sequence which binds to, and activates, antithrombin III (AT III) is a potent antithrombotic compound in several animal models of venous thrombosis. We describe here the preparation and the pharmacological properties of 34, an analogue of oligosaccharide 1 with the latter's N-sulfates being replaced by sulfate esters and hydroxyl groups being methylated. These structural modifications allow a simpler and more efficient synthesis of such anionic oligosaccharides. Affinity for human AT III, anti-factor Xa activity, ability to inhibit thrombin generation, antithrombotic activity in a rat model of venous thrombosis, and elimination half-life in the rat have been determined for 1 and 34. Surprisingly, introduction of O-sulfates in place of N-sulfates, and methylation of hydroxyl groups, contributes to reinforce the binding to AT III, resulting in an improved pharmacological profile.

References

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Citations

Aug 22, 2001·Trends in Biotechnology·S J Williams, G J Davies
May 18, 1999·Bioorganic & Medicinal Chemistry Letters·M PetitouJ M Herbert
Nov 13, 2001·Reviews in Clinical and Experimental Hematology·A GreinacherV Kiefel
Feb 11, 2005·European Journal of Clinical Investigation·S Alban
Jan 20, 2004·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Perumal Thiagarajan
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Jan 28, 2010·American Journal of Surgery·Sandra BattistelliTommaso Gori
Jul 26, 2005·Chemistry & Biology·Christian Noti, Peter H Seeberger
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Jan 6, 2004·Medicinal Research Reviews·Umesh R Desai
Aug 9, 2003·Blood·Alec MushunjeJames A Huntington
Mar 2, 2011·Journal of Molecular Recognition : JMR·Helena C CastroCarlos R Rodrigues
Mar 18, 2000·The Journal of Biological Chemistry·K J BelzarJ A Huntington
Apr 22, 2008·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Stephanie K A BlickLesley J Scott
Apr 6, 2001·Chemistry : a European Journal·M PetitouJ M Herbert
Mar 8, 2002·Journal of Medicinal Chemistry·Gunnar T Gunnarsson, Umesh R Desai

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