Edoxaban impurity

[1]. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost. 2008 Sep;6(9):1542-9.

[2]. The Effects of the Antiplatelet Agents, Aspirin and Naproxen, on Pharmacokinetics and Pharmacodynamics of the Anticoagulant Edoxaban, a Direct Factor Xa Inhibitor. J Cardiovasc Pharmacol. 2013 Apr 23.

Edoxaban is an oral factor Xa (FXa) inhibitor currently in clinical development for the prevention of stroke in patients with atrial fibrillation. Patients with atrial fibrillation are predominantly elderly and often take aspirin (ASA) and/or nonsteroidal anti-inflammatory drugs (NSAIDs) due to comorbidities. This study conducted three studies to evaluate the pharmacokinetic and pharmacodynamic interactions of 60 mg edoxaban in healthy subjects (n = 126) with low-dose (100 mg) ASA, high-dose (325 mg) ASA, or naproxen (500 mg). Bleeding time (BT) was measured. The mean baseline (pre-dose) BT ranged from 4.72 to 6.13 minutes across the three studies. Edoxaban alone increased BT by 21% to 35% from baseline at 4 hours post-dose. Edoxaban combined with high-dose aspirin, low-dose aspirin, or naproxen approximately doubled clotting time, demonstrating a greater additive effect than either drug alone. Low-dose aspirin or naproxen does not affect the pharmacokinetics of edoxaban, but high-dose aspirin can increase the systemic exposure of edoxaban by about 30%. The effects of edoxaban on prothrombin time, activated partial thromboplastin time, international normalized ratio, anti-FXa activity and endogenous FXa activity are not affected by aspirin or naproxen. Edoxaban does not affect the inhibitory effects of high-dose aspirin, low-dose aspirin or naproxen on platelet aggregation. Edoxaban is well tolerated in combination with aspirin or naproxen. [2]

---

Background: Coagulation factor Xa (FXa) is a key serine protease that converts prothrombin to thrombin in the coagulation cascade and is a promising target enzyme for the prevention and treatment of thromboembolic diseases. DU-176b is a novel antithrombotic drug that directly inhibits FXa activity. Objective: To evaluate the in vitro pharmacological properties and in vivo effects of DU-176b in animal models of thrombosis and hemorrhage. Methods: The inhibitory activity, specificity, and anticoagulant activity of FXa were detected in vitro. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail hemorrhage. Results: DU-176b showed a Ki value of 0.561 nM for free FXa and 2.98 nM for prothrombinase, exhibiting a selectivity for FXa exceeding 10,000-fold. In human plasma, DU-176b at concentrations of 0.256 μM and 0.508 μM doubled prothrombin time and activated partial thromboplastin time, respectively. DU-176b did not affect ADP, collagen, or U46619-induced platelet aggregation. DU-176b was well absorbed in rats and monkeys. After oral administration, its anti-Xa activity was stronger and the plasma drug concentration was higher than that of the original FXa inhibitor DX-9065a. In vivo experiments showed that DU-176b inhibited thrombosis in rat and rabbit thrombosis models in a dose-dependent manner, although bleeding time in rats was not significantly prolonged at the antithrombotic dose. Conclusion: Compared with the original drug DX-9065a, DU-176b is a more potent and selective FXa inhibitor with higher oral bioavailability. DU-176b is a promising new anticoagulant that can be used for the prevention and treatment of thromboembolic diseases. [1]

C21H30CLN5O5

467.95

467.193

480452-36-6

46911214

White to off-white solid powder

1.3±0.1 g/cm3

1.569

1.24

3

6

6

32

711

3

CC(C)(C)OC(=O)N[C@@H]1C[C@H](CC[C@@H]1NC(=O)C(=O)NC2=NC=C(C=C2)Cl)C(=O)N(C)C

YJDLJNAWLBVIRF-AEGPPILISA-N

InChI=1S/C21H30ClN5O5/c1-21(2,3)32-20(31)25-15-10-12(19(30)27(4)5)6-8-14(15)24-17(28)18(29)26-16-9-7-13(22)11-23-16/h7,9,11-12,14-15H,6,8,10H2,1-5H3,(H,24,28)(H,25,31)(H,23,26,29)/t12-,14-,15+/m0/s1

tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate

480452-36-6; tert-Butyl ((1R,2S,5S)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacetyl)amino)-5-(dimethylaminocarbonyl)cyclohexyl)carbamate; tert-Butyl [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl]carbamate; 836-116-0; Edoxaban impurity 4; tert-butyl (1R,2S,5S)-2-(2-(5-chloropyridin-2-ylamino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexylcarbamate; tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate; (1R, 2S, 5S)-tert-Butyl Edoxaban;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50 mg/mL (106.85 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)