Saroglitazar
(Synonyms: 沙罗格列扎) 目录号 : GC30379
A PPARα and PPARγ dual agonist
Cas No.:495399-09-2
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
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Animal experiment: |
Rats: Rats randomize based on body weights and are divided into three equal groups and receives the daily administration of vehicle (50% w/v honey for marmoset and 0.1% carboxymethylcellulose for Wistar rats) or Saroglitazar (1.5 and 15 mg/kg per day) for 90 days by oral gavage[1]. Mice: Male C57BL/6J-db/db mice are bled on day 0 to determine pretreatment serum glucose and TG. During next 12 days, each animal is dosed (by oral gavage) with vehicle (0.5% sodium carboxymethyl cellulose) or Saroglitazar (0.01, 0.03, 0.1, 0.3,1, and 3 mg/kg per day) or pioglitazone (60 mg/kg per day) and on day 12 of the treatment, blood samples are collected (1 h after dosing) from orbital sinus under light ether anesthesia. The serum is isolated and analyzed for glucose, TG, free fatty acid (FFA), and insulin levels[1]. |
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References: [1]. Jain MR, et al. Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models. Pharmacol Res Perspect. 2015 Jun;3(3):e00136. |
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Saroglitazar is a dual agonist of PPARα and PPARγ (EC50s = 0.65 and 3,000 pM, respectively, in a transactivation assay in HepG2 cells).1 It decreases serum triglyceride, free fatty acid, and glucose levels in a db/db mouse model of diabetes when administered at doses ranging from 0.01 to 3 mg/kg per day for 12 days. It increases insulin sensitivity in an oral glucose challenge when administered at a dose of 1 mg/kg in db/db mice, as well as decreases LDL levels in hApoB100/hCETP mice and in hamsters fed a high-fat high-cholesterol diet. Saroglitazar (10 ?M) reverses palmitic acid-induced decreases in the expression of superoxide dismutase 1 (SOD1), SOD2, glutathione peroxidase (GPX), and catalase and increases in TNF-α, IL-1β, and IL-6 expression in HepG2 cells.2 It decreases hepatic inflammation and steatosis in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a choline-deficient high-fat diet when administered at a dose of 3 mg/kg and inhibits fibrosis in a mouse model of fibrosis induced by carbon tetrachloride.
1.Jain, M.R., Giri, S.R., Trivedi, C., et al.Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical modelsPharmacol. Res. Perspect.3(3)e00136(2015) 2.Jain, M.R., Giri, S.R., Bhoi, B., et al.Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH modelsLiver Int.38(6)1084-1094(2018)
| Cas No. | 495399-09-2 | SDF | |
| 别名 | 沙罗格列扎 | ||
| Canonical SMILES | OC([C@@H](OCC)CC1=CC=C(OCCN2C(C)=CC=C2C3=CC=C(SC)C=C3)C=C1)=O | ||
| 分子式 | C25H29NO4S | 分子量 | 439.57 |
| 溶解度 | DMSO : ≥ 25 mg/mL (56.87 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 2.275 mL | 11.3748 mL | 22.7495 mL |
| 5 mM | 0.455 mL | 2.275 mL | 4.5499 mL |
| 10 mM | 0.2275 mL | 1.1375 mL | 2.275 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。
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Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial
Background and aims: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. Approach and results: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). Conclusions: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).
Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models
Background & aims: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH.
Methods & results: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride-induced fibrosis model.
Conclusions: Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.
The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease
Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPAR-target expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of NASH in humans.
Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis
Background & aim: Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual agonistic properties (α/γ). Due to a strong mechanistic rationale, we aimed to test the safety and efficacy of saroglitazar in patients with primary biliary cholangitis (PBC) who were either ursodeoxycholic acid (UDCA) resistant or intolerant.
Methods: In this double-blind, phase II proof-of-concept trial, 37 patients with PBC were randomized to saroglitazar 4 mg (n = 13), saroglitazar 2 mg (n = 14), or placebo (n = 10) daily for 16 weeks. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at Week 16.
Results: A significant reduction of mean ALP levels was observed at Week 16 relative to baseline in both the saroglitazar 4 mg (least-squares [LS] mean =-163.3 U/L, SE = 25.1, p <0.001) and 2 mg (LS mean =-155.8 U/L, SE = 24.4, p <0.001) groups, compared with placebo (LS mean =-21.1 U/L, SE = 28.9). Treatment with saroglitazar resulted in a rapid reduction of ALP concentration at Week 4 that was sustained through the study duration. At least 1 treatment-emergent adverse event occurred in 11 (84.6%) patients in the saroglitazar 4 mg group, in 12 (85.7%) patients in the 2 mg group and in 8 (80%) patients in the placebo group. Study drug was discontinued in 4 patients (3 patients in the 4 mg group and 1 patient in the 2 mg group) due to aminotransferase increases that promptly returned to baseline values after drug discontinuation.
Conclusions: Saroglitazar at 2 mg and 4 mg daily was tolerated and resulted in rapid and sustained improvements in ALP. Further studies are underway at a daily dose of 2 mg and 1 mg due to the higher incidence of elevated liver enzymes observed with the 4 mg dose. CLINICALTRIALS.
Gov identifier: NCT03112681 LAY SUMMARY: Saroglitazar resulted in a rapid and sustained improvement in alkaline phosphatase levels in patients with primary biliary cholangitis. The mean percentage reductions in alkaline phosphatase levels were 49% and 51% in the saroglitazar 4 mg and 2 mg groups compared to 3% in the placebo group.
Saroglitazar for the treatment of dyslipidemia in diabetic patients
Introduction: Diabetes and dyslipidemia are commonly associated modifiable risk factors for cardiovascular diseases. Majority of patients with diabetes also suffer from dyslipidemia (diabetic dyslipidemia). Diabetic dyslipidemia is more atherogenic as it is commonly associated with high triglyceride (TG) levels, high proportion of small dense low-density lipoprotein cholesterol and low high-density lipoprotein cholesterol (HDL-C) level (atherogenic dyslipidemia). Currently used pharmacotherapies for the management of diabetes and dyslipidemia like thiazolidinediones (PPAR-γ agonist; for insulin resistance) and fibrates (PPAR-α agonist; for hypertriglyceridemia) have many limitations and side effects. Saroglitazar , a dual PPAR-α/γ agonists, is an emerging therapeutic option with its dual benefit on glycemic and lipid parameters.
Areas covered: This paper reviews the clinical development of saroglitazar for the management of diabetic dyslipidemia. The efficacy and safety profile of saroglitazar is reviewed in context to currently available therapy like pioglitazone for diabetes and fibrates for hypertriglyceridemia. In addition, this paper also reviews the association between diabetes and dyslipidemia and the role of TG in reducing cardiovascular events.
Expert opinion: Saroglitazar, a dual PPAR-α/γ agonist, is a potential therapeutic option for the management of diabetic dyslipidemia. It has dual benefit of significant improvement in glycemic parameters (glycated hemoglobin and fasting blood glucose) and significant improvement in dyslipidemia (TGs, apolipoprotein B, non-HDL-C). The results of Phase III clinical trials indicate that saroglitazar is devoid of conventional side effects of fibrates and pioglitazone. Future clinical trials of saroglitazar will further establish its place in the management of diabetes, dyslipidemia and associated cardiovascular risk.