title: Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor.
abstract: Darexaban (YM150) is an oral factor Xa inhibitor developed for the prophylaxis of venous and arterial thromboembolic disease. This study was conducted to investigate the biochemical and pharmacological profiles of darexaban and its active metabolite darexaban glucuronide (YM-222714), which predominantly determines the antithrombotic effect after oral administration of darexaban. In vitro activity was evaluated by enzyme and coagulation assays, and a prothrombin activation assay using reconstituted prothrombinase or whole blood clot. In vivo effects were examined in venous thrombosis, arterio-venous (A-V) shunt thrombosis, and bleeding models in rats. Both darexaban and darexaban glucuronide competitively and selectively inhibited human factor Xa with Ki values of 0.031 and 0.020 μM, respectively. They showed anticoagulant activity in human plasma, with doubling concentrations of darexaban and darexaban glucuronide for prothrombin time of 1.2 and 0.95 μM, respectively. Anticoagulant activity was independent of antithrombin. Darexaban and darexaban glucuronide inhibited the prothrombin activation induced by prothrombinase complex or whole blood clot with similar potency to free factor Xa. In contrast, prothrombinase- and clot-induced prothrombin activation were resistant to inhibition by enoxaparin. In venous and A-V shunt thrombosis models in rats, darexaban strongly suppressed thrombus formation without affecting bleeding time, with ID₅₀ values of 0.97 and 16.7 mg/kg, respectively. Warfarin also suppressed thrombus formation in these models, but caused a marked prolongation of bleeding time at antithrombotic dose. In conclusion, darexaban is a selective and direct factor Xa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.
authors: Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yoshiyuki.iwatsuki@jp.astellas.com
authors: Yoshiyuki
authors: Y
authors: Iwatsuki
authors: Takayuki
authors: T
authors: Sato
authors: Yumiko
authors: Y
authors: Moritani
authors: Takeshi
authors: T
authors: Shigenaga
authors: Mami
authors: M
authors: Suzuki
authors: Tomihisa
authors: T
authors: Kawasaki
authors: Toshiyuki
authors: T
authors: Funatsu
authors: Seiji
authors: S
authors: Kaku
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001381:Azepines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001760:Bleeding Time; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D020719:Glucuronides / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology; D020246:Venous Thrombosis / Q000188:drug therapy / Q000503:physiopathology; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001381:Azepines; D001549:Benzamides; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D020719:Glucuronides; C570990:darexaban glucuronide; D014859:Warfarin; C569750:darexaban