Antithrombotic and anticoagulant profiles of TAK-442, a novel factor Xa inhibitor, in a rabbit model of venous thrombosis.

Abstract

The anticoagulant and antithrombotic profiles of TAK-442, a direct factor Xa (FXa) inhibitor, were investigated. TAK-442 showed potent inhibition of human FXa (Ki = 1.8 nM) and high specificity, with a 440-fold greater selectivity than thrombin and negligible effects on trypsin, plasmin, and tissue plasminogen activator (K(i) > 30 microM). [corrected] In human plasma, TAK-442 doubled FXa-induced clotting time, prothrombin time (PT), and activated partial thromboplastin time at 0.19, 0.55, and 0.59 microM, respectively. The relative PT-prolonging potencies of TAK-442, rivaroxaban, and apixaban were 1, 2.0-2.6, and 0.46-1.3, respectively, in 4 different PT reagents. In a rabbit model of venous thrombosis, 50- and 100-micrograms/kg [corrected] TAK-442 (intravenous bolus followed by 1-hour infusion) reduced thrombus formation by 50% and 81%, with plasma anti-FXa activity of 23%-26% and 34%-38%, respectively, and only marginal prolongation of PT and activated partial thromboplastin time. Melagatran, a thrombin inhibitor, showed similar antithrombotic activity to TAK-442. However, 500-micrograms/kg [corrected TAK-442 did not affect bleeding time (BT), whereas the same dose of melagatran significantly prolonged BT by 3.6-fold compared with vehicle control. These findings suggest that TAK-442 has similar antithrombotic effects as melagatran but does not cause BT prolongation, and plasma anti-FXa activity may reliably predict its potency.

• Authors: Masaki Kawamura, Noriko Konishi, Katsuhiko Hiroe, Ken-ichi Shofuda, Yasuhiro Imaeda, Takuya Fujimoto, Keiji Kubo
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 56 Issue 2 Pg. 156-61 (Aug 2010) ISSN: 1533-4023 [Electronic] United States
• PMID: 20410831 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 1-(1-(3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoyl)piperidin-4-yl)tetrahydropyrimidin-2(1H)-one
• Anticoagulants
• Azetidines
• Benzylamines
• Factor Xa Inhibitors
• Fibrinolytic Agents
• Morpholines
• Pyrazoles
• Pyridones
• Pyrimidinones
• Sulfones
• Thiophenes
• melagatran
• apixaban
• Rivaroxaban
• Thrombin

Topics

• Animals
• Anticoagulants (pharmacology, therapeutic use)
• Azetidines (pharmacology)
• Benzylamines (pharmacology)
• Bleeding Time
• Blood Coagulation (drug effects)
• Blood Coagulation Tests
• Dogs
• Factor Xa Inhibitors
• Fibrinolytic Agents (pharmacology, therapeutic use)
• Humans
• Macaca fascicularis
• Male
• Mice
• Mice, Inbred ICR
• Morpholines (pharmacology)
• Pyrazoles (pharmacology)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology, therapeutic use)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Rivaroxaban
• Sulfones (pharmacology, therapeutic use)
• Thiophenes (pharmacology)
• Thrombin (antagonists & inhibitors)
• Venous Thrombosis (blood, drug therapy)