Darexaban
(Synonyms: N-[2-羟基-6-(4-甲氧基苯甲酰氨基)苯基]-4-(4-甲基-1,4-二氮杂庚烷-1-基)苯甲酰胺,YM150) 目录号 : GC62922
Darexaban (YM150) 是一种有效、选择性和具有口服活性的 Xa 因子 (FXa) 抑制剂，IC50 为 54.6 nM。Darexaban 对其他相关丝氨酸蛋白酶（如胰蛋白酶、凝血酶和激肽释放酶）显示出高选择性。Darexaban 具有抗凝和抗血栓形成作用。
Cas No.:365462-23-3
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Darexaban (YM150) is a potent, selective and orally active factor Xa (FXa) inhibitor with an IC50 of 54.6 nM. Darexaban shows high selectivity against other related serine proteases, such as trypsin, thrombin, and kallikrein. Darexaban has anticoagulant and antithrombotic effects[1][2][3].
Darexaban is an oral direct factor Xa (FXa) inhibitor that is rapidly and extensively metabolized into its glucuronide conjugate (YM-222714) post-administration. Darexaban competitively and selectively inhibits human FXa, and also inhibits the prothrombin activation induced by prothrombinase complex or whole blood clot with similar potency to free FXa[2].
In mice, Darexaban inhibits FXa activity in plasma with an ED50 value of 24.8 mg/kg. Darexaban prolonges prothrombin time (PT) at 3 mg/kg[2]. In a pulmonary thromboembolism (PE) mouse model, Darexaban dose-dependently reduces the mortality rate, significantly so at 10 mg/kg[2]. In a FeCl3-induced venous thrombosis (VT) mouse model, Darexaban (0.3-10 mg/kg) dose-dependently decreases the thrombus protein content, significantly so at doses of 3 mg/kg or higher[2].
[1]. Fukushi Hirayama, et al. Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor. J Med Chem. 2011 Dec 8;54(23):8051-65.
[2]. Seiji Kaku, et al. Darexaban: anticoagulant effects in mice and human plasma in vitro, antithrombotic effects in thrombosis and bleeding models in mice and effects of anti-inhibitor coagulant complex and recombinant factor VIIa. Thromb Res. 2013 May;131(5):450-6.
[3]. Milan Remko, et al. Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors. Molecules. 2016 Feb 4;21(2):185.
| Cas No. | 365462-23-3 | SDF | |
| 别名 | N-[2-羟基-6-(4-甲氧基苯甲酰氨基)苯基]-4-(4-甲基-1,4-二氮杂庚烷-1-基)苯甲酰胺,YM150 | ||
| 分子式 | C27H30N4O4 | 分子量 | 474.55 |
| 溶解度 | DMSO : 250 mg/mL (526.81 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.1073 mL | 10.5363 mL | 21.0726 mL |
| 5 mM | 0.4215 mL | 2.1073 mL | 4.2145 mL |
| 10 mM | 0.2107 mL | 1.0536 mL | 2.1073 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Darexaban: anticoagulant effects in mice and human plasma in vitro, antithrombotic effects in thrombosis and bleeding models in mice and effects of anti-inhibitor coagulant complex and recombinant factor VIIa
Thromb Res 2013 May;131(5):450-6.PMID:23591155DOI:10.1016/j.thromres.2013.03.016.
Here, we investigated the anticoagulant effects of Darexaban in mice and human plasma in vitro, effects of Darexaban in thrombosis and bleeding models in mice, and reversal effects of anti-inhibitor coagulant complex (ACC) and recombinant factor VIIa (rFVIIa) on anticoagulant effects of Darexaban. In mice, Darexaban inhibited FXa activity in plasma with an ED50 value of 24.8 mg/kg. Both Darexaban and warfarin prolonged prothrombin time (PT) at 3 mg/kg and 0.3 mg/kg/day, respectively. PT and activated partial thromboplastin time (aPTT) prolonged by Darexaban were dose-dependently reversed by intravenously-administered rFVIIa, significantly so at 1 mg/kg. In a pulmonary thromboembolism (PE) mouse model, both Darexaban and warfarin dose-dependently reduced the mortality rate, significantly so at 10 mg/kg and 3 mg/kg/day, respectively. In a FeCl3-induced venous thrombosis (VT) mouse model, Darexaban (0.3-10 mg/kg) dose-dependently decreased the thrombus protein content, significantly so at doses of 3 mg/kg or higher. In a tail-transection mouse model, Darexaban had no significant effect on the amount of blood loss at doses up to 10 mg/kg, while warfarin showed a dose-dependent increase in blood loss, significantly so from 1 mg/kg/day. Darexaban and its metabolite Darexaban glucuronide significantly prolonged PT and aPTT in human plasma in vitro, and while rFVIIa concentration-dependently reversed the prolonged PT in this plasma, ACC dose-dependently reversed both PT and aPTT changes prolonged by Darexaban. Taken together, these results suggest that Darexaban has a potential to be an oral anticoagulant with a better safety profile than warfarin, and that rFVIIa and ACC may be useful as antidotes to Darexaban in cases of overdose.
Novel oral anticoagulants: focus on the direct factor Xa inhibitor Darexaban
Expert Opin Investig Drugs 2012 Jul;21(7):1057-64.PMID:22616561DOI:10.1517/13543784.2012.689286.
Introduction: Inhibition of the pathways of anticoagulation is widely used for the prevention and treatment of arterial and venous thrombosis. Vitamin K antagonists (VKAs) have been the mainstay of oral anticoagulation for more than 60 years. Their safety and effectiveness have been established in multiple clinical trials, for a variety of clinical indications. However, there are several limitations to the use of VKAs including delayed onset of action and dosage titration, numerous food and drug interactions and need for regular laboratory monitoring. To overcome some of the limitations of traditional agents, new oral anticoagulants (OACs) have been developed and evaluated. Areas covered: In the present review article, the pharmacokinetic properties of Darexaban are presented, along with the available preliminary clinical data. The performance of Darexaban in respect to safety and efficacy compared with its competitors is further discussed. Expert opinion: Darexaban is a potent direct factor Xa inhibitor that demonstrated impressive pharmacokinetic properties in pre-clinical studies. It was further successfully evaluated in the ONYX program for the prevention of venous thromboembolism in patients undergoing hip replacement. Finally, in the Phase II RUBY-1 trial, Darexaban was tested on the top of standard antiplatelet therapy for the prevention of ischemic events in acute coronary syndrome (ACS) patients. Despite the fact that Darexaban had a relatively uneventful clinical evaluation program, its further development was recently discontinued. This decision could probably reflect the non-favorite results in commercially attractive indications, such as secondary prevention post-ACS and the increased competition for less common or short-term indications such stroke prevention in AF or VTE prophylaxis respectively.
Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin
Eur J Drug Metab Pharmacokinet 2014 Mar;39(1):1-9.PMID:23754514DOI:10.1007/s13318-013-0141-1.
To investigate the impact of the direct Factor Xa inhibitor Darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and Darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6-7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin C max,ss and AUC0-24h,ss with and without darexaban-MR co-administration were within 0.80-1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for C max,ss and AUC0-24h,ss of digoxin plus Darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94-1.12) and 1.11 (90 % CI: 1.05-1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80-1.25, indicating a lack of drug-drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin.
Darexaban for the prevention of venous thromboembolism in Asian patients undergoing orthopedic surgery: results from 2 randomized, placebo-controlled, double-blind studies
Clin Appl Thromb Hemost 2014 Mar;20(2):199-211.PMID:22952213DOI:10.1177/1076029612457810.
Objective: To evaluate the efficacy and safety of Darexaban (YM150) in Asian patients undergoing total hip or total knee arthroplasty. Methods: In 2 phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies, patients were randomized to oral Darexaban 15 mg twice daily (bid), Darexaban 30 mg bid, oral placebo bid, or subcutaneous enoxaparin 20 mg bid. Primary efficacy outcome for both studies was total venous thromboembolism (VTE) incidence. Results: Both Darexaban doses were statistically significantly superior to placebo for total VTE incidence (hip study: Darexaban 15 mg bid [2.9%] vs placebo [17.1%], P < .001; Darexaban 30 mg bid [5.2%] vs placebo [17.1%], P = .003; and knee study: Darexaban 15 mg bid [27.2%] vs placebo [52.8%], P = .002; Darexaban 30 mg bid [15.5%] vs placebo [52.8%], P < .001). In both studies, the incidence of bleeding events was low across all treatment groups. Conclusion: Darexaban is effective and well tolerated as VTE prophylaxis in Asian patients undergoing elective major orthopedic surgery.
Biochemical and pharmacological profile of Darexaban, an oral direct factor Xa inhibitor
Eur J Pharmacol 2011 Dec 30;673(1-3):49-55.PMID:22040919DOI:10.1016/j.ejphar.2011.10.009.
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.