Emricasan
(Synonyms: 恩利卡生; PF 03491390; IDN-6556) 目录号 : GC35980
A pan-caspase inhibitor
Cas No.:254750-02-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Animal experiment: |
Mice[2] The male C57BL/6J mice are age-matched and used at approximately 12-16 weeks of age. Four groups are studied (n=60) with 15 mice per group. Groups 1 and 3 receive regular chow. Groups 2 and 4 receive HFD and 50 g/L (Sucrose) is added to drinking water for 20 weeks. Groups 3 and 4 receive Emricasan 0.3 mg/kg/day per os, and Group 1 and 2 receive the vehicle. The oral administration of Emricasan at doses of 0.3 mg/kg corresponds to the ED90 value to prevent liver injury in the model of α-Fas-induced liver injury. Total body weight is measured at 0, 5, 10, 15 and 20 weeks. Rats[3] The male Sprague-Dawley rats are cannulated in the carotid artery under isoflurane anesthesia and allowed to recover for at least 1 day before drug administration. Blood (100 μL/sample) is taken from the carotid cannula 2 to 240 min after administration of Emricasan (i.v., s.c., p.o., or i.p.). Serum is prepared and frozen immediately until analysis. In studies measuring drug concentrations in portal and systemic blood, individual rats are bled (three animals per time point) simultaneously from the portal vein and inferior vena cava. In the biliary excretion study, bile is collected from the common bile duct after i.v. and p.o. administration of Emricasan (10 mg/kg) over a 24-h period on ice and frozen until analysis. |
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References: [1]. Gracia-Sancho J, et al. Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism. Hepatol Commun. 2019 Apr 22;3(7):987-1000. |
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Emricasan is a pan-caspase inhibitor.1,2,3,4 Ex vivo, emricasan (10 mg/kg) prevents cold ischemia-warm reperfusion-induced sinusoidal endothelial cell (SEC) apoptosis and inhibits caspase-3 activation in rat liver by 55 and 94%, respectively.1 In vivo, emricasan reduces alanine aminotransferase (ALT) levels (ED50s = <0.01-0.38 mg/kg) as well as apoptosis and caspase activity in a dose-dependent manner in the α-Fas mouse and D-Gln/LPS rat models of liver injury.2 Emricasan reduces caspase-3 and caspase-8 activity, serum ALT levels, hepatocyte apoptosis, and hepatic fibrogenesis in a mouse model of high-fat diet-induced non-alcoholic steatohepatitis (NASH).3 It also enhances islet engraftment and lowers post-transplant fasting glucose levels in a porcine islet autotransplant model.4
1.Natori, S., Higuchi, H., Contreras, P., et al.The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injuryLiver Transpl.9(3)278-284(2003) 2.Hoglen, N.C., Chen, L.S., Fisher, C.D., et al.Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid): A liver-targeted caspase inhibitorJ. Pharmacol. Exp. Ther.309(2)634-640(2004) 3.Barreyro, F.J., Holod, S., Finocchietto, P.V., et al.The pan-caspase inhibitor emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitisLiver Int.35(3)953-966(2015) 4.McCall, M.D., Maciver, A.M., Kin, T., et al.Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant modelTransplantation94(1)30-35(2012)
| Cas No. | 254750-02-2 | SDF | |
| 别名 | 恩利卡生; PF 03491390; IDN-6556 | ||
| Canonical SMILES | FC1=C(C(F)=C(C=C1F)F)OCC([C@@H](NC([C@@H](NC(C(NC2=C(C=CC=C2)C(C)(C)C)=O)=O)C)=O)CC(O)=O)=O | ||
| 分子式 | C26H27F4N3O7 | 分子量 | 569.5 |
| 溶解度 | DMSO: ≥ 42 mg/mL (73.75 mM) | 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 | 1.7559 mL | 8.7796 mL | 17.5593 mL |
| 5 mM | 0.3512 mL | 1.7559 mL | 3.5119 mL |
| 10 mM | 0.1756 mL | 0.878 mL | 1.7559 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。
Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis
J Hepatol 2021 Feb;74(2):274-282.PMID:33038432DOI:10.1016/j.jhep.2020.09.029.
Background & aims: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to Emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results: There was no difference in event rates between either of the Emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of Emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of Emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that Emricasan might improve portal hypertension and liver function. In this larger randomized study, Emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. Gov identifier: NCT03205345.
The impact of Emricasan on chronic liver diseases: current data
Clin J Gastroenterol 2022 Apr;15(2):271-285.PMID:35000120DOI:10.1007/s12328-021-01585-2.
Immoderate caspase-mediated apoptosis in chronic liver injury is a crucial driver of sustained HSC activation and worsening hepatic inflammation as well as fibrosis, with the ultimate outcome of liver cirrhosis and its consequences. Therefore, the inhibition of hepatocyte apoptosis by caspase cascade blockage may be a promising therapeutic strategy to achieve fibrosis regression in chronic liver diseases. Emricasan is a broad-spectrum, liver-targeted caspase inhibitor with a favorable pharmacokinetic profile, characterized by prolonged retention in the liver and low systemic exposure after oral administration. In animal models, Emricasan had a clear intrahepatic anti-apoptotic effect with consequent elimination of circulating pro-inflammatory cytokines and favorable impact in liver fibrogenesis and portal pressure. Even though, this intrahepatic drug effect confirmed in human clinical trials, no clear linkage was emerged with portal hypertension, liver function or liver histology in both non-cirrhotic and cirrhotic patients except from a subgroup of patients with high MELD score (> 15) or severe HVPG (> 16 mmHg). As Emricasan treatment appeared safe and well-tolerated, irrespective the severity of liver disease, more studies are required to clarify better these subgroups of patients who may benefit most from this drug.
Current and future pharmacological therapies for NAFLD/NASH
J Gastroenterol 2018 Mar;53(3):362-376.PMID:29247356DOI:10.1007/s00535-017-1415-1.
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator-activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and Emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.
Efficacy and Safety of Emricasan in Liver Cirrhosis and/or Fibrosis
Clinics (Sao Paulo) 2021 Jun 14;76:e2409.PMID:34133478DOI:10.6061/clinics/2021/e2409.
This study aimed to perform a meta-analysis to determine the efficacy and safety of Emricasan. Nine databases were searched for clinical trials investigating the efficacy of Emricasan treatment in patients with liver cirrhosis or fibrosis. A manual search was conducted to identify the missing trials. The quality of the included studies was assessed using the revised Cochrane risk of bias tool. Efficacy of Emricasan treatment was defined as a positive change in apoptosis-related parameters from baseline to the last follow-up visit. Overall, Emricasan treatment is more effective in patients with liver cirrhosis or fibrosis than placebo (standardized mean difference [SMD] [95% confidence intervals (CI)]=0.28 [0.14; 0.41]). No significant change in model for end-stage liver disease (MELD) score between the Emricasan and placebo groups was noted (SMD [95% CI]=0.18 [-0.01; 0.36]; p=0.058). A 50 mg dose of Emricasan had the highest efficacy rate compared to placebo (SMD [95% CI]=0.28 [0.06; 0.50]; p=0.012), followed by the 5 mg dosing regimen (SMD [95% CI]=0.28 [0.06; 0.50]; p=0.012). Treatment with Emricasan resulted in significant reductions in ALT (mean difference (MD) [95% CI]=-5.89 [-10.59; -1.20]; p=0.014) and caspase3/7 levels (MD [95%CI]=-1215.93 [-1238.53; -1193.33]; p<0.001), respectively. No significant increase in the rate of overall adverse events was noted (OR [95% CI]=1.52 [0.97; 2.37]; p=0.069). Treatment with Emricasan is more effective in improving liver function and apoptosis parameters compared to placebo, with a well-tolerated safety profile. However, due to the poor quality of the analyzed studies, the small number of trials and patients, and the short follow-up periods, more robust trials are still warranted.
Efficacy and safety of drugs for nonalcoholic steatohepatitis
J Dig Dis 2021 Feb;22(2):72-82.PMID:33385317DOI:10.1111/1751-2980.12967.
Nonalcoholic steatohepatitis (NASH) is an inflammatory type of nonalcoholic fatty liver disease and is associated with the development and progression of cirrhosis. Lifestyle intervention is still the predominant treatment for NASH. So far, no drugs have been approved to treat NASH by the U.S. Food and Drug Administration (FDA). Vitamin E has been recommended for patients with NASH without type 2 diabetes mellitus (T2DM), whereas a combination of pioglitazone and vitamin E is recommended for patients with both NASH and T2DM. Encouragingly, drugs are currently being developed for different NASH mechanisms. Some of the drugs are at phase III clinical trials, including obeticholic acid (OCA), Elafibranor, Cenicriviroc, Selonsertib, Resmetirom, Emricasan and Aramchol. Due to its positive interim effect in attenuating the degree of hepatic fibrosis OCA was filing in FDA. However, it has been rejected by the U.S FDA and has been advised to conduct long-term studies. Therefore, in this article, we reviewed the efficacy and safety of drugs currently under clinical trials for NASH.