title: 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.affiliation: Takeda Global Research & Development Center Inc, Deerfield, IL 60015, USA. mkawamura@tgrd.com
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamura
authors.forename: Noriko
authors.initials: N
authors.lastname: Konishi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hiroe
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Shofuda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imaeda
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Kubo
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D000069552:Rivaroxaban; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy*
chemical_list: C553657:1-(1-(3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoyl)piperidin-4-yl)tetrahydropyrimidin-2(1H)-one; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D011720:Pyrazoles; D011728:Pyridones; D011744:Pyrimidinones; D013450:Sulfones; D013876:Thiophenes; C109573:melagatran; C522181:apixaban; D000069552:Rivaroxaban; D013917:Thrombin