Synthesis and pharmacological properties of a close analogue of an antithrombotic pentasaccharide (SR 90107A/ORG 31540).
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.
Petitou
M
M
Haemobiology Research Department, Sanofi Recherche, Toulouse, France. maurice.petitou@tls1.elfsanofi.fr
Duchaussoy
P
P
Jaurand
G
G
Gourvenec
F
F
Lederman
I
I
Strassel
J M
JM
Bârzu
T
T
Crépon
B
B
Hérault
J P
JP
Lormeau
J C
JC
Bernat
A
A
Herbert
J M
JM
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
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