Icosabutate
(Synonyms: PRB 01022, PRC 4016) 目录号 : GC40485
A synthetic ω-3 PUFA
Cas No.:1253909-57-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Icosabutate is a synthetic ω-3 polyunsaturated fatty acid derived from eicosapentaenoic alcohol and 2-bromo butyric acid. It was designed to resist β-oxidation and complex lipid incorporation and increase efficacy in fatty acid-responsive intracellular signaling systems. In a clinical trial, oral administration of icosabutate (600 mg) significantly reduced triglyceride, very low-density lipoprotein cholesterol, and Apo c-III levels in patients with very high triglyceride levels.
| Cas No. | 1253909-57-7 | SDF | |
| 别名 | PRB 01022, PRC 4016 | ||
| Canonical SMILES | CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(O)=O | ||
| 分子式 | C24H38O3 | 分子量 | 374.6 |
| 溶解度 | 0.1 M Na2CO3: 1.7 mg/ml,DMF: 100 mg/ml,DMSO: 100 mg/ml,Ethanol: miscible | 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 | 2.6695 mL | 13.3476 mL | 26.6951 mL |
| 5 mM | 0.5339 mL | 2.6695 mL | 5.339 mL |
| 10 mM | 0.267 mL | 1.3348 mL | 2.6695 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。
A structurally engineered fatty acid, Icosabutate, suppresses liver inflammation and fibrosis in NASH
J Hepatol 2022 Apr;76(4):800-811.PMID:34915054DOI:10.1016/j.jhep.2021.12.004.
Background & aims: Although long-chain omega-3 fatty acids (LCn-3FAs) regulate inflammatory pathways of relevance to non-alcoholic steatohepatitis (NASH), their susceptibility to peroxidation may limit their therapeutic potential. We compared the metabolism of eicosapentaenoic acid (EPA) with an engineered EPA derivative (Icosabutate) in human hepatocytes in vitro and their effects on hepatic glutathione metabolism, oxidised lipids, inflammation, and fibrosis in a dietary mouse model of NASH, and in patients prone to fatty liver disease. Methods: Oxidation rates and cellular partitioning of EPA and Icosabutate were compared in primary human hepatocytes. Comparative effects of delayed treatment with either low- (56 mg/kg) or high-dose (112 mg/kg) Icosabutate were compared with EPA (91 mg/kg) or a glucagon-like peptide 1 receptor agonist in a choline-deficient (CD), L-amino acid-defined NASH mouse model. To assess the translational potential of these findings, effects on elevated liver enzymes and fibrosis-4 (FIB-4) score were assessed in overweight, hyperlipidaemic patients at an increased risk of NASH. Results: In contrast to EPA, Icosabutate resisted oxidation and incorporation into hepatocytes. Icosabutate also reduced inflammation and fibrosis in conjunction with a reversal of CD diet-induced changes in the hepatic lipidome. EPA had minimal effect on any parameter and even worsened fibrosis in association with depletion of hepatic glutathione. In dyslipidaemic patients at risk of NASH, Icosabutate rapidly normalised elevated plasma ALT, GGT and AST and reduced FIB-4 in patients with elevated ALT and/or AST. Conclusion: Icosabutate does not accumulate in hepatocytes and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidaemic patients, these findings suggest that structural engineering of LCn-3FAs offers a novel approach for the treatment of NASH. Lay summary: Long-chain omega-3 fatty acids are involved in multiple pathways regulating hepatic inflammation and fibrosis, but their susceptibility to peroxidation and use as an energy source may limit their clinical efficacy. Herein, we show that a structurally modified omega-3 fatty acid, Icosabutate, overcame these challenges and had markedly improved antifibrotic efficacy in a mouse model of non-alcoholic steatohepatitis. A hepatoprotective effect of Icosabutate was also observed in patients with elevated circulating lipids, in whom it led to rapid reductions in markers of liver injury.
Icosabutate: targeting metabolic and inflammatory pathways for the treatment of NASH
Expert Opin Investig Drugs 2022 Dec;31(12):1269-1278.PMID:36527256DOI:10.1080/13543784.2022.2159804.
Introduction: Via pleiotropic targeting of membrane and nuclear fatty acid receptors regulating key metabolic and inflammatory pathways in the liver, long-chain omega-3 fatty acids could offer a unique therapeutic approach for the treatment of metabolic-inflammatory diseases such as NASH. However, they lack efficacy for the treatment of NASH, likely due to unfavorable distribution, metabolism, and susceptibility to peroxidation. Areas covered: Structurally engineered fatty acids (SEFAs), as exemplified by Icosabutate, circumvent the inherent limitations of unmodified long-chain fatty acids, and demonstrate markedly enhanced pharmacodynamic effects without sacrificing safety and tolerability. We cover Icosabutate's structural modifications, their rationale and the fatty acid receptor and pathway targeting profile. We also provide an overview of the clinical data to date, including interim data from a Phase 2b trial in NASH subjects. Expert opinion: Ideally, candidate drugs for NASH and associated liver fibrosis should be pleiotropic in mechanism and work upstream on multiple drivers of NASH, including lipotoxic lipid species, oxidative stress, and key modulators of inflammation, liver cell injury, and fibrosis. Icosabutate has demonstrated the ability to target these pathways in preclinical NASH models with interim data from the ICONA trial supporting, at least noninvasively, the clinical translation of highly promising pre-clinical data.
Icosabutate Exerts Beneficial Effects Upon Insulin Sensitivity, Hepatic Inflammation, Lipotoxicity, and Fibrosis in Mice
Hepatol Commun 2019 Dec 24;4(2):193-207.PMID:32025605DOI:10.1002/hep4.1453.
Icosabutate is a structurally engineered eicosapentaenoic acid derivative under development for nonalcoholic steatohepatitis (NASH). In this study, we investigated the absorption and distribution properties of Icosabutate in relation to liver targeting and used rodents to evaluate the effects of Icosabutate on glucose metabolism, insulin resistance, as well as hepatic steatosis, inflammation, lipotoxicity, and fibrosis. The absorption, tissue distribution, and excretion of Icosabutate was investigated in rats along with its effects in mouse models of insulin resistance (ob/ob) and metabolic inflammation/NASH (high-fat/cholesterol-fed APOE*3Leiden.CETP mice) and efficacy was compared with synthetic peroxisome proliferator-activated receptor α (PPAR-α) (fenofibrate) and/or PPAR-γ/(α) (pioglitazone and rosiglitazone) agonists. Icosabutate was absorbed almost entirely through the portal vein, resulting in rapid hepatic accumulation. Icosabutate demonstrated potent insulin-sensitizing effects in ob/ob mice, and unlike fenofibrate or pioglitazone, it significantly reduced plasma alanine aminotransferase. In high-fat/cholesterol-fed APOE*3Leiden.CETP mice, Icosabutate, but not rosiglitazone, reduced microvesicular steatosis and hepatocellular hypertrophy. Although both rosiglitazone and Icosabutate reduced hepatic inflammation, only Icosabutate elicited antifibrotic effects in association with decreased hepatic concentrations of multiple lipotoxic lipid species and an oxidative stress marker. Hepatic gene-expression analysis confirmed the changes in lipid metabolism, inflammatory and fibrogenic response, and energy metabolism, and revealed the involved upstream regulators. In conclusion, Icosabutate selectively targets the liver through the portal vein and demonstrates broad beneficial effects following insulin sensitivity, hepatic microvesicular steatosis, inflammation, lipotoxicity, oxidative stress, and fibrosis. Icosabutate therefore offers a promising approach to the treatment of both dysregulated glucose/lipid metabolism and inflammatory disorders of the liver, including NASH.
Icosabutate for the treatment of very high triglycerides: A placebo-controlled, randomized, double-blind, 12-week clinical trial
J Clin Lipidol 2016 Jan-Feb;10(1):181-91.e1-2.PMID:26892135DOI:10.1016/j.jacl.2015.10.012.
Background: Icosabutate is a structurally enhanced omega-3 fatty acid molecule developed with the aim of achieving improved triglyceride (TG)-lowering efficacy, increased potency, and preserved safety compared with conventional prescription omega-3 fatty acid. Objective: To evaluate the efficacy and safety of Icosabutate 600 mg once daily in patients with very high TGs. Methods: After a 6-8 week run-in period, men and women with TG levels ≥ 500 mg/dL and ≤ 1500 mg/dL were randomized to double-blind treatment with placebo or Icosabutate 600 mg for 12 weeks. The primary end point was % change from baseline in TGs at 12 weeks. Results: A total of 87 subjects were randomized. At baseline, median TG (interquartile range) levels were 611 (543-878) and 688 (596-892) mg/dL, and the median change after 12 weeks of treatment was -51% and -17%, respectively, for a placebo-corrected change of -33% (P < .001). Adjusted for placebo, Icosabutate significantly reduced very low-density lipoprotein cholesterol (-36%, P < .001), remnant lipoprotein cholesterol (-34%, P < .001), apolipoprotein (Apo) C-III (-35%, P < .001), trended toward reduced non-high-density lipoprotein cholesterol (-7%, P = .064); significantly increased high-density lipoprotein cholesterol (18%, P < .001) and low-density lipoprotein cholesterol (28%, P < .001), with a trend of an increased lipoprotein (a; 10%, P = .054). No changes were observed in total cholesterol, apolipoprotein B, or apolipoprotein A1. Fasting plasma glucose was unchanged, whereas fasting plasma insulin was reduced (P = .001) with Icosabutate. Icosabutate was generally well tolerated. Conclusion: Treatment with Icosabutate once daily significantly reduced TG, very low-density lipoprotein cholesterol, and Apo C-III levels in patients with very high TG levels. This trial was registered at www.clinicaltrials.gov as NCT01893515.
Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia
Cardiology 2016;135(1):3-12.PMID:27160246DOI:10.1159/000445047.
Objectives: To evaluate the efficacy and safety of Icosabutate, an oral, once-daily, first-in-class medication, in reducing non-high-density lipoprotein cholesterol (non-HDL-C) in patients with persistent hypertriglyceridemia despite statin therapy. Methods: The study was designed to randomly assign 140 patients with fasting triglyceride levels ≥200 but <500 mg/dl on a stable dose of statin therapy to receive either masked Icosabutate 600 mg once daily or a control for 12 weeks. The primary end point was a percentage change in non-HDL-C from baseline to 12 weeks. Results: With Icosabutate, non-HDL-C levels were reduced (-9.2%) when compared with the control (-0.4%) for a between-group difference of -7.4% (p = 0.02). Compared with the control, Icosabutate reduced triglycerides (-27.0%, p < 0.001), very- low-density lipoprotein (VLDL) cholesterol (-31.5%, p < 0.001) and apolipoprotein C-III (-22.5%, p < 0.001). LDL-C levels did not change (0.5%, p = 0.87). HDL-C (10.2%, p < 0.001) was increased. After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of Icosabutate in a dog study. In this study, adverse events were balanced between treatment arms, and there were no discontinuations due to adverse events. Conclusions: Icosabutate was efficacious in lowering non-HDL-C and other biomarkers of cardiovascular risk and was generally well tolerated.