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Lemborexant Sale

(Synonyms: 莱博雷生,E-2006) 目录号 : GC19220

Lemborexant (E2006) is an oral active diorexin receptor antagonist (DORA) and has been approved by the US Food and Drug Administration for the treatment of insomnia.

Lemborexant Chemical Structure

Cas No.:1369764-02-2

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥2,574.00
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5mg
¥2,340.00
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10mg
¥4,050.00
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25mg
¥7,200.00
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Sample solution is provided at 25 µL, 10mM.

产品文档

Quality Control & SDS

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实验参考方法

Animal experiment [1]:

Animal models

Men and women 19 to 80 years of age (insomnia disorder)

Preparation Method

The medication was administered 30 minutes before bedtime.

Dosage form

1-25mg;15days

Applications

Lemborexant had a positive effect on Sleep Efficiency (SE) by improving both sleep onset (decreasing LPS) and sleep maintenance (decreasing WASO) in a dose-related manner.

References:

[1]. Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi L, Satlin A. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017 Nov 15;13(11):1289-1299. doi: 10.5664/jcsm.6800. PMID: 29065953; PMCID: PMC5656478.

产品描述

Lemborexant (E2006) is an oral active diorexin receptor antagonist (DORA) and has been approved by the US Food and Drug Administration for the treatment of insomnia[1-2].

Lemborexant(1-25mg;15days) had a positive effect on Sleep Efficiency (SE) by improving both sleep onset (decreasing LPS) and sleep maintenance (decreasing WASO) in a dose-related manner[2]. In 62 subjects, according to circadian rhythm, day and night parameters (placebo, n = 12; lemborexant 2.5 mg [LEM2.5], n = 12; lemborexant 5 mg [LEM5], n = 13, lemborexant 10 mg [LEM10], n = 13 and lemborexant 15 mg [LEM15], n = 12). Mean least active 5 hours (L5) showed a decrease from baseline to week 4 for LEM2.5, LEM5 and LEM15 that was significantly greater than with placebo, suggesting a reduction in restlessness[3].

References:
[1]. Dayvigo [prescribing information] (lemborexant), Woodcliff Lake, NJ: Eisai Inc. US. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf. Accessed January 08, 2020.
[2]. Murphy P, Moline M, et,al. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017 Nov 15;13(11):1289-1299. doi: 10.5664/jcsm.6800. PMID: 29065953; PMCID: PMC5656478.
[3]. Moline M, Thein S, et,al. Safety and Efficacy of Lemborexant in Patients With Irregular Sleep-Wake Rhythm Disorder and Alzheimer's Disease Dementia: Results From a Phase 2 Randomized Clinical Trial. J Prev Alzheimers Dis. 2021;8(1):7-18. doi: 10.14283/jpad.2020.69. PMID: 33336219.

Lemborexant (E2006) 是一种口服活性双食欲素受体拮抗剂 (DORA),已获得美国食品和药物管理局批准用于治疗失眠[1-2]。

Lemborexant(1- 25 毫克;15 天)通过以剂量相关的方式改善入睡(降低 LPS)和睡眠维持(降低 WASO),对睡眠效率 (SE) 产生积极影响 [2]。在 62 名受试者中,根据昼夜节律、昼夜参数(安慰剂,n = 12;lemborexant 2.5 mg [LEM2.5],n = 12;lemborexant 5 mg [LEM5],n = 13,lemborexant 10 mg [LEM10] , n = 13 和 lemborexant 15 mg [LEM15], n = 12)。 LEM2.5、LEM5 和 LEM15 的平均最少活动 5 小时 (L5) 显示从基线到第 4 周的减少明显大于安慰剂,表明躁动减少[3]。

Chemical Properties

Cas No. 1369764-02-2 SDF
别名 莱博雷生,E-2006
Canonical SMILES O=C([C@H]1[C@@](C2=CC=CC(F)=C2)(COC3=CN=C(C)N=C3C)C1)NC4=NC=C(F)C=C4
分子式 C22H20F2N4O2 分子量 410.42
溶解度 DMSO : ≥ 30 mg/mL (73.10 mM) 储存条件 Store at -20°C
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溶解性数据

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1 mM 2.4365 mL 12.1826 mL 24.3653 mL
5 mM 0.4873 mL 2.4365 mL 4.8731 mL
10 mM 0.2437 mL 1.2183 mL 2.4365 mL
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Research Update

Lenvatinib: A Review in Hepatocellular Carcinoma

Lenvatinib (Lenvima?) is an oral small molecule inhibitor of multiple receptor tyrosine kinases, and is approved for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC) in the USA, EU, Japan and China. The approval of lenvatinib was based on results of the randomized, open-label, multinational, non-inferiority phase III REFLECT trial in patients with unresectable HCC, who had not received treatment for advanced disease. In REFLECT, lenvatinib was non-inferior, but not superior, to sorafenib (current standard of care) for overall survival (OS). However, lenvatinib was associated with significant improvements compared with sorafenib in terms of all secondary endpoints [higher objective response rate (ORR), and longer progression-free survival (PFS) and time to progression (TTP)]. Lenvatinib had a generally manageable tolerability profile in REFLECT, with the most common treatment-emergent adverse events being hypertension, diarrhoea, decreased appetite and decreased weight. Given its non-inferior efficacy to sorafenib and manageable tolerability profile, lenvatinib represents a long-awaited alternative option to sorafenib for the first-line systemic treatment of patients with unresectable HCC. Further clinical experience may be required to fully define the position of lenvatinib in this setting.

Lenvatinib versus placebo in radioiodine-refractory thyroid cancer

Background: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).
Methods: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.
Results: The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.
Conclusions: Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy

Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma (HCC). Its application has changed the status of sorafenib as the only first-line TKI treatment for HCC for more than a decade. Evidence has shown that lenvatinib possesses antitumor proliferation and immunomodulatory activity in preclinical studies. In comparison, lenvatinib was non-inferior to sorafenib in overall survival (OS), and even shows superiority with regard to all the secondary efficacy endpoints. Immune-checkpoint inhibitors(ICIs)are now being incorporated into HCC treatment. Positive outcomes have been achieved in the combination of lenvatinib plus ICIs, bringing broader prospects for HCC. This review presents an overview on the therapeutic mechanisms and clinical efficacy of lenvatinib in HCC, and we discuss the future perspectives of lenvatinib in HCC management with focus on biomarker-guided precision medicine.

Lenvatinib Targets FGF Receptor 4 to Enhance Antitumor Immune Response of Anti-Programmed Cell Death-1 in HCC

Background and aims: Recently, clinical trials of lenvatinib plus pembrolizumab in HCC have displayed an impressive objective response rate. This study aimed to clarify the mechanism for optimal patient selection.
Approach and results: First, in patients with HCC, lenvatinib-treated recurrent tumors had lower programmed death ligand 1 (PD-L1) expression and regulatory T cell (Treg) infiltration compared with matched primary tumors. Consistently, in C57BL/6 wild-type mice receiving anti-programmed cell death 1 (PD-1) therapy, PD-L1 expression and Treg infiltration in s.c. tumors were reduced when adding lenvatinib to the scheme. Mechanistically, on the one hand, FGF receptor 4 (FGFR4) was the most pivotal target in PD-L1 down-regulation by lenvatinib in vitro. Furthermore, lenvatinib reinforced the proteasomal degradation of PD-L1 by blocking the FGFR4-glycogen synthase kinase 3β axis and rescued the sensitivity of interferon-γ-pretreated HCC cells to T-cell killing by targeting FGFR4. On the other hand, the level of IL-2 increased after anti-PD-1 treatment, but IL-2-mediated Treg differentiation was blocked by lenvatinib through targeting FGFR4 to restrain signal transducer and activator of transcription 5 (STAT5) phosphorylation. By regulating the variations in the number of Tregs and the tumor FGFR4 level in C57BL/6-forkhead box protein P3 (Foxp3DTR ) mice, we found that high levels of FGFR4 and Treg infiltration sensitized tumors to the combination treatment. Finally, high levels of FGFR4 and Foxp3 conferred immune tolerance but better response to the combined therapy in patient cohorts.
Conclusions: Lenvatinib reduced tumor PD-L1 level and Treg differentiation to improve anti-PD-1 efficacy by blocking FGFR4. Levels of FGFR4 expression and Treg infiltration in tumor could serve as biomarkers for screening patients with HCC using lenvatinib plus anti-PD-1 combination therapy.

STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib

Background: Dysregulation of both mitochondrial biogenesis and mitophagy is critical to sustain oncogenic signaling pathways. However, the mechanism of mitophagy in promoting hepatocellular carcinoma (HCC) progression remains poorly understood. In this study, we investigated the clinical significance and biological involvement of mitochondrial inner membrane protein STOML2 in HCC.
Methods: STOML2 was identified by gene expression profiles of HCC tissues and was measured in tissue microarray and cell lines. Gain/loss-of-function experiment was applied to study the biological function of STOML2 in HCC. Flow cytometry, Western blotting, laser confocal microscopy, transmission electron microscopy, and co-immunoprecipitation were used to detect and analyze mitophagy. ChIP and luciferase reporter assay were conducted to evaluate the relationship between STOML2 and HIF-1α. The sensitivity to lenvatinib was assessed in HCC both in vitro and in vivo.
Results: Increased expression of STOML2 was found in HCC compared with paired peritumoral tissues. It was more significant in HCC with metastasis and correlated with worse overall survival and higher probability of recurrence after hepatectomy. Upregulation of STOML2 accelerated HCC cells colony formation, migration and invasion. Mechanically, TCGA dataset-based analysis showed enrichment of autophagy-related pathways in STOML2 highly-expressed HCC. Next, STOML2 was demonstrated to interact and stabilize PINK1 under cellular stress, amplify PINK1-Parkin-mediated mitophagy and then promote HCC growth and metastasis. Most interestingly, HIF-1α was upregulated and transcriptionally increased STOML2 expression in HCC cells under the treatment of lenvatinib. Furthermore, higher sensitivity to lenvatinib was found in HCC cells when STOML2 was downregulated. Combination therapy with lenvatinib and mitophagy inhibitor hydroxychloroquine obtained best efficacy.
Conclusions: Our findings suggested that STOML2 could amplify mitophagy through interacting and stabilizing PINK1, which promote HCC metastasis and modulate the response of HCC to lenvatinib. Combinations of pharmacologic inhibitors that concurrently block both angiogenesis and mitophagy may serve as an effective treatment for HCC.