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Liraglutide Sale

(Synonyms: 利拉鲁肽) 目录号 : GC10311

A potent agonist of the GLP-1 receptor

Liraglutide Chemical Structure

Cas No.:204656-20-2

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Quality Control & SDS

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实验参考方法

Kinase experiment [1]:

Preparation Method

A cloned human GLP-1 receptor expressed in juvenile hamster kidney (BHK) cells was used, Study on functional assays of compounds( Liraglutide ) using SAR.

Reaction Conditions

10-14 -10-5 M liraglutide

Applications

Liraglutide is a highly potent, long-acting GLP-1 receptor agonistand and shares 97% of its amino acid sequence identity with human GLP-1 (EC50 = 61 pM).

Cell experiment [2]:

Cell experiment

HepG2 cell line

Preparation Method

Cell viability assay :HepG2 cells were seeded onto a 96-well plate, then treated with PA and LPS in the presence of liraglutide (0, 50, 100, 200, 500 nM) for 16 h. The number of viable cells was determined using Cell Counting Kit-8 (CCK-8)

Reaction Conditions

liraglutide (0, 50, 100, 200, 500 nM) for 16 h

Applications

The number of viable cells in hepatocytes treated with PA/LPS was significantly reduced, and liraglutide reversed the decline in cell viability in a concentration-dependent manner. Liraglutide at 100 nM significantly increased cell viability compared with higher concentrations.

Animal experiment [3]:

Animal models

Male ApoE KO mice on C57BL/6 background

Preparation Method

Liraglutide (1 mg/kg) or saline was given intraperitoneally twice daily for 8 weeks (from 9th to 16th week of HFD feeding)

Dosage form

Liraglutide (1 mg/kg) for 8 weeks

Applications

Liraglutide treatment improved insulin sensitivity and increased Acrp30 plasma levels and transcriptional activity, Liraglutide treatment reduces liver fat content, Liraglutide was sufficient to protect mice from the inflammatory consequences of HFD and Acrp30 knockdown.

References:

[1]. Knudsen LB, Nielsen PF,et,al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000 May 4;43(9):1664-9. doi: 10.1021/jm9909645. PMID: 10794683

[2]. Yu X, Hao M, et,al. Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol. 2019 Dec 1;864:172715. doi: 10.1016/j.ejphar.2019.172715. Epub 2019 Oct 5. PMID: 31593687.

[3]. Zhang L, Yang M, et,al. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int. 2013 May;33(5):794-804. doi: 10.1111/liv.12120. Epub 2013 Feb 24. PMID: 23432843.

产品描述

Liraglutide is a highly potent, long-acting GLP-1 receptor agonist (EC50 = 61 pM)and shares 97% of its amino acid sequence identity with human GLP-1 [6,7].

The number of viable cells in hepatocytes treated with PA/LPS was significantly reduced, and liraglutide reversed the decline in cell viability in a concentration-dependent manner. Liraglutide at 100 nM significantly increased cell viability compared with higher concentrations[1].In H9c2 cardiomyoblasts,Pretreatment with 100 nM liraglutide could efficiently inhibit TNF-α and hypoxia-induced inflammasome activation. liraglutide reversed the level of SIRT1,Liraglutide diminished the levels of ROS generation and NOX4 expression[2]. Liraglutide relieved steatosis by improving hepatic fat synthesis, transportation, storage, and use via PI3K and AMPK pathways [3].The cytoplasmic lipid droplet accumulation was visibly decreased in foam cells by treatment with liraglutide. The TG and cholesterol content in the liraglutide-treated foam cells was significantly decreased. Expression level of AMPKα1 and phosphorylated AMPKα1 was significantly increased while the expression level of SREBP1 and phosphorylated SREBP1 was significantly decreased in foam cells following treatment with liraglutide[5].

In mice,The combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS)[4].

References:
[1]: Yu X, Hao M, et,al. Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol. 2019 Dec 1;864:172715. doi: 10.1016/j.ejphar.2019.172715. Epub 2019 Oct 5. PMID: 31593687.
[2]: Chen A, Chen Z, et,al. Liraglutide attenuates NLRP3 inflammasome-dependent pyroptosis via regulating SIRT1/NOX4/ROS pathway in H9c2 cells. Biochem Biophys Res Commun. 2018 May 5;499(2):267-272. doi: 10.1016/j.bbrc.2018.03.142. Epub 2018 Mar 23. PMID: 29571736.
[3]: Liu J, Wang G, et,al. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diabetes Metab Res Rev. 2015 May;31(4):329-35. doi: 10.1002/dmrr.2580. Epub 2014 Sep 14. PMID: 25066109.
[4]: Zhang L, Yang M, et,al. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int. 2013 May;33(5):794-804. doi: 10.1111/liv.12120. Epub 2013 Feb 24. PMID: 23432843.
[5]: Wang YG, Yang TL. Liraglutide reduces oxidized LDL-induced oxidative stress and fatty degeneration in Raw 264.7 cells involving the AMPK/SREBP1 pathway. J Geriatr Cardiol. 2015 Jul;12(4):410-6. doi: 10.11909/j.issn.1671-5411.2015.04.013. PMID: 26346224; PMCID: PMC4554794.
[6]: Bode B. Liraglutide: a review of the first once-daily GLP-1 receptor agonist. Am J Manag Care. 2011 Mar;17(2 Suppl):S59-70. PMID: 21517658.
[7]: Knudsen LB, Nielsen PF, et,al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000 May 4;43(9):1664-9. doi: 10.1021/jm9909645. PMID: 10794683.

利拉鲁肽是一种高效、长效的 GLP-1 受体激动剂 (EC50 = 61 pM),其氨基酸序列与人 GLP-1 有 97% 的同一性[6,7] .

用 PA/LPS 处理的肝细胞中的活细胞数量显着减少,利拉鲁肽以浓度依赖性方式逆转细胞活力的下降。与更高浓度相比,100 nM 利拉鲁肽可显着提高细胞活力[1]。在 H9c2 心肌细胞中,100 nM 利拉鲁肽预处理可有效抑制 TNF-α 和缺氧诱导的炎性体激活。 liraglutide 逆转 SIRT1 水平,Liraglutide 降低 ROS 生成和 NOX4 表达水平[2]。利拉鲁肽通过 PI3K 和 AMPK 通路改善肝脏脂肪的合成、运输、储存和使用,从而减轻脂肪变性[3]。利拉鲁肽处理后,泡沫细胞中的细胞质脂滴积累明显减少。利拉鲁肽处理的泡沫细胞中的甘油三酯和胆固醇含量显着降低。利拉鲁肽处理后泡沫细胞中AMPKα1和磷酸化AMPKα1的表达水平显着升高,而SREBP1和磷酸化SREBP1的表达水平显着降低[5]

在小鼠中,HFD、Acrp30 敲低和 ApoE 缺陷的组合对胰岛素抵抗 (IR) 和 NAFLD 的发展具有累加效应。在该模型中,利拉鲁肽的给药阻止了 HFD 和低脂联素血症诱导的 IR 和 NAFLD 的发展。利拉鲁肽还减弱促炎细胞因子或转录因子的表达,包括 TNF-α 和 NF-κB(65),以及两种脂肪生成相关基因乙酰辅酶 A 羧化酶 (ACC) 和脂肪酸合酶 (FAS) 的表达[4].

Chemical Properties

Cas No. 204656-20-2 SDF
别名 利拉鲁肽
Canonical SMILES CCCCCCCCCCCCCCCC(=O)NC(CCC(=O)NCCCCC(C(=O)NC(CCC(=O)O)C(=O)NC(CC1=CC=CC=C1)C(=O)NC(C(C)CC)C(=O)NC(C)C(=O)NC(CC2=CNC3=CC=CC=C32)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(=N)N)C(=O)NCC(=O)NC(CCCNC(=N)N)C(=O)NCC(=O)O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(=O)N)NC(
分子式 C172H265N43O51 分子量 3751.20
溶解度 <20mg/mL in Water, ≥ 3.85mg/mL in Acetic acid:Water:DMSO=1:1:1 储存条件 Store at -20°C,protect from light
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1 mM 0.2666 mL 1.3329 mL 2.6658 mL
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Research Update

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial

Background: Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss. Methods: We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide [0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks] or liraglutide [3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week]) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711. Findings: Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102-103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was -2·3% for the placebo group versus -6·0% (0·05 mg), -8·6% (0·1 mg), -11·6% (0·2 mg), -11·2% (0·3 mg), and -13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p≤0·0010), and remained significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all significant (-13·8% to -11·2% vs -7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37-65% receiving 0·1 mg or more of semaglutide (p<0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists. Interpretation: In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses. Funding: Novo Nordisk A/S.

A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity

Background: Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity.
Methods: In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56.
Results: A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment.
Conclusions: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).

Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined

Background: Weight regain after weight loss is a major problem in the treatment of persons with obesity.
Methods: In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous-intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.
Results: After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, -4.1 kg (95% confidence interval [CI], -7.8 to -0.4; P = 0.03); in the liraglutide group, -6.8 kg (95% CI, -10.4 to -3.1; P<0.001); and in the combination group, -9.5 kg (95% CI, -13.1 to -5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, -5.4 kg; 95% CI, -9.0 to -1.7; P = 0.004) but not liraglutide (-2.7 kg; 95% CI, -6.3 to 0.8; P = 0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (-1.7 percentage points; 95% CI, -3.2 to -0.2; P = 0.02) and the liraglutide group (-1.9 percentage points; 95% CI, -3.3 to -0.5; P = 0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group.
Conclusions: A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.).

Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study

Background: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.
Methods: This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119.
Findings: Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]).
Interpretation: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
Funding: Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

Liraglutide: A New Option for the Treatment of Obesity

Obesity continues to pose a major public health risk to the United States and across the world, with an estimated one-third of adult Americans being defined as obese. Obesity treatment guidelines recommend the use of pharmacologic therapy in adults who have a body mass index (BMI) of 30 kg/m(2) or higher or in patients with a BMI of 27 kg/m(2) or higher who have at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, insulin resistance, type 2 diabetes mellitus). Liraglutide is a glucagon-like peptide-1 receptor agonist that has been successfully used in the treatment of type 2 diabetes for several years. Weight loss has been well described as an additional benefit with liraglutide therapy, which prompted the manufacturer to evaluate and develop a higher dose formulation specifically for the treatment of obesity. Liraglutide 3 mg/day was approved by the U.S. Food and Drug Administration for this indication in December 2014. We performed a search of the Medline database to identify relevant literature focused on liraglutide's role specifically in treating obesity. Five clinical trials with this primary end point were identified. Data demonstrated that liraglutide can successfully achieve weight-loss benchmarks of 5% or more and 10% or more loss from baseline. The most common adverse effects were gastrointestinal and mild to moderate in intensity. The cost of therapy is high, averaging over $1000/month for out-of-pocket expenses if insurance coverage is not available. Liraglutide is also available for delivery only by subcutaneous injection, which may represent a barrier for patients. Liraglutide 3 mg/day represents another pharmacologic option for the treatment of obesity.