title: Synthesis and pharmacological properties of a close analogue of an antithrombotic pentasaccharide (SR 90107A/ORG 31540).
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.
authors.affiliation: Haemobiology Research Department, Sanofi Recherche, Toulouse, France. maurice.petitou@tls1.elfsanofi.fr
authors.forename: M
authors.initials: M
authors.lastname: Petitou
authors.forename: P
authors.initials: P
authors.lastname: Duchaussoy
authors.forename: G
authors.initials: G
authors.lastname: Jaurand
authors.forename: F
authors.initials: F
authors.lastname: Gourvenec
authors.forename: I
authors.initials: I
authors.lastname: Lederman
authors.forename: J M
authors.initials: JM
authors.lastname: Strassel
authors.forename: T
authors.initials: T
authors.lastname: Bârzu
authors.forename: B
authors.initials: B
authors.lastname: Crépon
authors.forename: J P
authors.initials: JP
authors.lastname: Hérault
authors.forename: J C
authors.initials: JC
authors.lastname: Lormeau
authors.forename: A
authors.initials: A
authors.lastname: Bernat
authors.forename: J M
authors.initials: JM
authors.lastname: Herbert
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009844:Oligosaccharides; C064764:PENTA; D013431:Sulfates; C106268:methyl O-(3,4-di-O-methyl-2,6-di-O-sulfoglucopyranosyl)-1-4-O-(2,3-di-O-methylglucopyranosyluronic acid)-1-4-O-(2,3,6-tri-O-sulfoglucopyranosyl)-1-4-O-(3-O-methyl-2-O-sulfoidopyranosyluronic acid)-(1-4)-3-O-methyl-2,6-di-O-sulfoglucopyranoside; D000990:Antithrombin III; D013917:Thrombin