Atopaxar
(Synonyms: 2-(5,6-二乙氧基-7-氟-1,3-二氢-1-亚氨基-2H-异吲哚-2-基)-1-[3-叔丁基-4-甲氧基-5-(4-吗啉基)苯基]乙酮,E5555; ER-172594-00) 目录号 : GC63658
Atopaxar(E5555,ER-172594-00) is a potent, orally active, selective and reversible thrombin receptor protease-activated receptor-1 (PAR-1) antagonist.
Cas No.:751475-53-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Atopaxar(E5555,ER-172594-00) is a potent, orally active, selective and reversible thrombin receptor protease-activated receptor-1 (PAR-1) antagonist.
[1] Dockendorff C, et al. ACS Med Chem Lett. 2012 Mar 8;3(3):232-237.
| Cas No. | 751475-53-3 | SDF | |
| 别名 | 2-(5,6-二乙氧基-7-氟-1,3-二氢-1-亚氨基-2H-异吲哚-2-基)-1-[3-叔丁基-4-甲氧基-5-(4-吗啉基)苯基]乙酮,E5555; ER-172594-00 | ||
| 分子式 | C29H38FN3O5 | 分子量 | 527.63 |
| 溶解度 | DMSO : 250 mg/mL (473.82 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8953 mL | 9.4763 mL | 18.9527 mL |
| 5 mM | 0.3791 mL | 1.8953 mL | 3.7905 mL |
| 10 mM | 0.1895 mL | 0.9476 mL | 1.8953 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。
Atopaxar
Hamostaseologie 2012;32(3):228-233.PMID:29589364DOI:10.5482/HAMO-12-05-0009.
Atopaxar, also known as E 5555 is a novel reversible protease-activated receptor-1 (PAR-1) thrombin receptor antagonist. To date, Atopaxar has been investigated in phase II trials with focus on safety and tolerability in patients with acute coronary syndromes or stable coronary artery disease on top of standard antiplatelet therapy. Atopaxar was generally well tolerated, however a rise in liver enzymes and prolongation of the QTcF interval were observed. The data suggest, that Atopaxar administration may promote some minor bleeding complications, but does not seem to significantly increase the risk of major bleeding. Although not powered for efficacy, the currently available data suggest potential benefits in patients at high risk for recurrent ischemic events on top of standard antiplatelet therapy. In conclusion, more studies (e.g. phase III) are needed to evaluate efficacy and safety of Atopaxar.
Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program
J Thromb Thrombolysis 2012 Jul;34(1):36-43.PMID:22653705DOI:10.1007/s11239-012-0750-6.
Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of Atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to Atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by -553 (95 % CI -677, -429) ng/L in the combined Atopaxar group versus -30.3 (-249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA(2) mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined Atopaxar group as compared with 2.6 (95 % CI -2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the Atopaxar group versus a -1.2 (95 % CI -10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of Atopaxar on Lp-PLA(2) and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, Atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although Atopaxar increased the concentration of Lp-PLA(2) and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.
Atopaxar: a review of its mechanism of action and role in patients with coronary artery disease
Future Cardiol 2012 Jul;8(4):503-11.PMID:22871190DOI:10.2217/fca.12.35.
Platelet activation and aggregation is a complex and key process in thrombus formation after the rupture of an atherosclerotic plaque, which can lead to an acute coronary syndrome. Aspirin, an irreversible inhibitor of thromboxane A(2) synthesis, in combination with an inhibitor of P2Y(12) ADP platelet receptors (clopidogrel, prasugrel or ticagrelor), represents the current standard of care of antiplatelet therapy for patients with acute coronary syndrome and in those patients undergoing percutaneous coronary intervention. Despite the benefit of these agents, the risk of thrombotic events and bleeding complications may still occur while on such antiplatelet treatment regimens, thus representing an important limitation. Thrombin is one of the most important platelet activators. The inhibition of thrombin-mediated platelet activation by means of protease-activated receptor-1 inhibitors represents an attractive therapeutic option for patients with atherothrombotic disease processes. This article provides an overview on Atopaxar (E5555), an orally active protease-activated receptor-1 antagonist that has recently completed Phase II clinical investigation.
Discovery and evaluation of Atopaxar hydrobromide, a novel JAK1 and JAK2 inhibitor, selectively induces apoptosis of cancer cells with constitutively activated STAT3
Invest New Drugs 2020 Aug;38(4):1003-1011.PMID:31612426DOI:10.1007/s10637-019-00853-w.
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a vital role in immunity, cell division, cell death and tumor formation. Disrupted JAK-STAT signaling may lead to various diseases, especially cancer and immune disorders. Because of its importance, this signaling pathway has received significant attention from the pharmaceutical and biotechnology industries as a therapeutic target for drug design. However, few JAK or STATs inhibitors have been developed for cancer treatment. We used an in vitro STAT3 luciferase reporter assay to find novel inhibitors that could effectively block the JAK-STAT pathway. In our study, we screened 16,081 drug-like chemicals and found that Atopaxar hydrobromide (AHB) is a specific inhibitor of JAK-STAT3 signaling. Our results suggest that AHB not only blocks constitutively activated and cytokine-induced STAT3 phosphorylation but also inhibits JAK1 and JAK2 phosphorylation. Moreover, AHB induces G1 phase cell cycle arrest, which stops cancer cell growth and induces apoptosis. AHB also inhibited tumor cell growth in vivo. In conclusion, AHB is a potential inhibitor that could be developed as a JAK-STAT pathway drug.
Randomized trial of Atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin–Coronary Artery Disease Trial
Circulation 2011 May 3;123(17):1854-63.PMID:21502571DOI:10.1161/CIRCULATIONAHA.110.001404.
Background: Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with Atopaxar in subjects with CAD. Methods and results: Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of Atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with Atopaxar compared with placebo by CURE criteria (placebo, 0.6%; Atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; Atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the Atopaxar subjects. All Atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose Atopaxar treatment groups. Conclusions: In this dose-ranging study of patients with CAD, treatment with Atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects. Clinical trial registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.