title: Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activity.
abstract: Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man.
authors.affiliation: Scientific Development Group, N.V. Organon, Oss, the Netherlands. gerard.vogel@organon.com
authors.forename: G M T
authors.initials: GM
authors.lastname: Vogel
authors.forename: D G
authors.initials: DG
authors.lastname: Meuleman
authors.forename: T G
authors.initials: TG
authors.lastname: Van Dinther
authors.forename: R
authors.initials: R
authors.lastname: Buijsman
authors.forename: A W M
authors.initials: AW
authors.lastname: Princen
authors.forename: M J
authors.initials: MJ
authors.lastname: Smit
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000077425:Fondaparinux; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009844:Oligosaccharides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010875:Pipecolic Acids / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009844:Oligosaccharides; C485125:Org 42675; D010875:Pipecolic Acids; D011134:Polysaccharides; D013449:Sulfonamides; D000990:Antithrombin III; D006493:Heparin; D001120:Arginine; D013917:Thrombin; C031942:argatroban; D000077425:Fondaparinux