Antifactor Xa activity and antithrombotic activity in rats of structural analogues of the minimum antithrombin III binding sequence: discovery of compounds with a longer duration of action than of the natural pentasaccharide.
The total chemical synthesis of a series of structural analogues of the so-called natural AT III binding pentasaccharide together with the natural pentasaccharide itself has been accomplished. The structural analogues all contain an extra 3-O-sulfate group on glucosamine residue H of the pentasaccharide, some carry additional 3 or 4-O-sulfate groups on glucosamine residue D. All these structural analogues elicit a higher specific anti-Factor Xa activity than the natural pentasaccharide (700 anti-Factor Xa U/kg). The structural analogue carrying only an additional 3-O-sulfate on glucosamine unit H (Org 31550) has the highest specific activity (1230 anti-Factor Xa U/kg). The increased specific activity is presumably attributed to the stronger binding to AT III. All structural analogues have a prolonged duration of action of the plasma anti-Factor Xa activity. (T1/2, approximately 9 hours) compared with that of the natural pentasaccharide (T1/2, approximately 5 hours) after single intravenous administration of 600 anti-Factor Xa U/kg. All structural analogues exert dose-dependent antithrombotic activity in a rat stasis thrombosis model after intravenous administration. On an anti-Factor Xa basis, the compounds have the same potency as the natural pentasaccharide (ED50s are 35 to 55 anti-factor Xa U/kg). Of two structural analogues (Org 31550 and Org 31706), the time course of antithrombotic activity was assessed in the same model after subcutaneous administration of 600 anti-Factor Xa U/kg. The duration of antithrombotic activity of these compounds was four to five times longer than that of the natural pentasaccharide.
Meuleman
D G
DG
Scientific Development Group, Organon International B.V., Oss, The Netherlands.
Hobbelen
P M
PM
Van Dinther
T G
TG
Vogel
G M
GM
Van Boeckel
C A
CA
Moelker
H C
HC
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000990:Antithrombin III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006493:Heparin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; C069688:ORG 31550; C069689:ORG 31706; D009844:Oligosaccharides; C064764:PENTA; C049714:IC 831423; D000990:Antithrombin III; D006493:Heparin