PPAR-α (IC50 = 45 nM); PPAR-δ (IC50 = 175 nM)

体外活性：Elafibranor（也称为 GFT505）正在开发作为 PPAR-α/PPAR-δ 双重激动剂，用于治疗 T2DM 和非酒精性脂肪肝疾病。 GFT505 具有活性代谢物 GFT1007，两者均对 PPAR-α 具有有效的激动剂活性，对 PPAR-δ 激酶测定具有较小程度的激动剂活性：Elafibranor 是一种 PPARα/δ 激动剂，EC50 分别为 45 和 175 nM。 GFT505 正在开发作为 PPAR-α/PPAR-δ 双重激动剂，用于治疗 T2DM 和非酒精性脂肪肝。 GFT505 具有活性代谢物 GFT1007，两者均对 PPAR-α 具有有效的激动剂活性，对 PPAR-δ 具有较小程度的激动剂活性。

Elafibranor（也称为 GFT505）是一种 PPARα/δ 双重激动剂，已在非酒精性脂肪性肝病 (NAFLD)/NASH 和肝纤维化疾病模型中显示出疗效。在大鼠中，GFT505 集中在肝脏中，肝外暴露有限，并经历了广泛的肠肝循环。 Elafibranor 通过作用于 NASH 发病机制中的多个途径来保护肝脏，减少脂肪变性、炎症和纤维化。 GFT505 改善肝功能障碍标志物，减少肝脏脂质积累，并抑制促炎症（白细胞介素 1 β、肿瘤坏死因子 α 和 F4/80）和促纤维化（转化生长因子 β、金属蛋白酶 2 组织抑制剂、I 型胶原、α 1）和 I 型胶原蛋白、α 2) 基因表达。

---

在意向治疗分析中，在方案定义的主要结局中，elafbranor组和安慰剂组之间没有显著差异。然而，与安慰剂组相比，120mg埃拉布诺组患者中NASH缓解而无纤维化恶化的比例更高(19% vs 12%；优势比= 2.31；95%置信区间：1.02-5.24；P = 0.045)，基于修改后定义的事后分析。在非酒精性脂肪性肝病活动度评分≥4的患者（n = 234）的事后分析中，根据方案定义，依非布兰120mg缓解NASH的患者比例高于安慰剂(20% vs 11%；优势比= 3.16；95%置信区间：1.22-8.13；P = 0.018)和修改后的定义(19% vs 9%；优势比= 3.52；95%置信区间：1.32-9.40；P = .013)。接受艾非布诺120mg治疗后，NASH缓解的患者与NASH未缓解的患者相比，肝纤维化分期减少(主要终点应答者平均减少0.65±0.61，无应答者平均减少0.10±0.98；P < 0.001)。与安慰剂组相比，elafbranor 120 mg组的肝酶、血脂、葡萄糖谱和全身炎症标志物显著降低。Elafibranor耐受性良好，没有引起体重增加或心脏事件，但确实产生了轻度的、可逆的血清肌酐升高(与安慰剂相比，效应大小：增加4.31±1.19 μmol/L；P < 0.001)。 结论：对NASH患者试验数据的事后分析显示，根据修改的定义，在意向治疗分析和中度或重度NASH患者中，依非布诺（120mg /d，持续1年）可缓解NASH，无纤维化恶化。然而，在治疗人群的意图中，没有达到预定的终点。elafbranor耐受性良好，改善了患者的心脏代谢风险概况。ClinicalTrials.gov编号：NCT01694849.[2]

---

Elafibranor在体外减弱了NASH的关键特征，并显著降低了脂质负荷以及炎症趋化因子的表达和分泌，炎症趋化因子在体内负责免疫细胞的募集。这种炎症反应的减少是由nfκ b介导的。总之，这种与人类相关的体外系统被证明是研究新型抗nash化合物的敏感测试工具。［4］

Elafibranor 是 PPARα/δ 的激动剂，EC50 值依次为 45 和 175 nM。作为 PPAR-α/PPAR-δ 双重激动剂，GFT505 正在开发用于治疗非酒精性脂肪肝和 2 型糖尿病。 GFT505 的活性代谢物 GFT1007 对 PPAR-α 具有很强的激动剂活性，对 PPAR-δ 具有较小程度的激动剂活性。

hSKP-HPC细胞培养及脂肪变性和NASH体外模型的建立[4]
hSKP是在获得父母的知情同意和布鲁塞尔大学医学伦理委员会的批准后，从1至10岁的小男孩包皮环切术样本中分离出来的。这些细胞被培养并分化为肝细胞样细胞（hSKP-HPC），如先前文献所述。 通过将hSKP-HPC（24 h）暴露于胰岛素（100 nM）和葡萄糖（4.5 mg/mL），体外模拟脂肪变性。同时暴露于油酸钠（65 μM）和棕榈酸（45 μM）（24 h），并联合促炎(50 ng/mL肿瘤坏死因子（TNF)- α + 25 ng/mL白细胞介素(IL)-1β）[19]和促纤维化（8 ng/mL转化生长因子(TGF)-β1）细胞因子混合物，形成NASH条件。油酸钠与7% （w/v）无牛血清白蛋白（BSA）脂肪酸络合。用二甲亚砜（DMSO）溶解棕榈酸和elafibranor 。细胞同时暴露于NASH触发器和elafibranor （10 μM和30 μM）。所有样品中BSA和DMSO的最终浓度分别为0.14% （w/v）和0.15% (v/v)(除了油酸钠和棕榈酸浓度的测定（如图1A和B所示），其中分别使用1.4% （w/v) BSA和0.5% (v/v) DMSO）。

---

用于测定细胞因子和趋化因子的抗体阵列[4]
收集对照样本和暴露于NASH诱导剂和elafibranor （10 μM和30 μM）的细胞的新鲜细胞培养基，使用人细胞因子抗体阵列（120 Targets） 根据制造商的方案检测白细胞介素和趋化因子的分泌。使用Chemidoc™MP系统对杂交斑点进行可视化。采用Image Lab 5.0软件进行半定量数据分析（n = 5，除hSKP-HPC NASH +elafibranor 30 μM: n = 3）。

hApoE2 KI and hApoE2 KI/PPAR-α KO mice
30 mg/kg
oral gavage

---

Researchers report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.[3]

---

Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score.[2]

Hepatotoxicity
In preregistration clinical trials, elafibranor was found to decrease both serum aminotransferase and alkaline phosphatase elevations in a high proportion of patients with PBC. In preliminary dose-finding studies in healthy volunteers, elevations of ALT and AST levels above 5 times the upper limit of normal (ULN) were found to be dose related and occurred in one-third of subjects exposed to doses above 120 mg daily. In contrast, in clinical trials of elafibranor in doses of 80 mg daily in patients with NASH and PBC, ALT elevations above 5 times ULN occurred in only 1% to 2% of patients, typically arising within the first few months of therapy and resolving spontaneously without drug interruption and without jaundice or symptoms. Careful assessment of cases with ALT elevations concluded that 3 were possibly due to drug induced injury, 2 among 138 patients with PBC and 1 among 1433 patients with NASH. Among patients with myalgia and CPK elevations during elafibranor therapy, one patient with preexisting cirrhosis who was also taking a statin, developed jaundice [5.5 mg/dL] with elevations in ALT [300 U/L] and AST [828 U/L] concurrent with rhabdomyolysis [CPK 12,647 U/L] and subsequently suffered hepatic decompensation. The incidence of gallstones and cholecystitis also may be increased with elafibranor therapy. Rare instances of drug induced liver injury are known to occur with other PPARα (fenofibrate, bezafibrate) and PPARγ (pioglitazone, rosiglitazone) agonists.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

[1]. Early investigational drugs targeting PPAR-α for the treatment of metabolic disease.Expert Opin Investig Drugs. 2015 May;24(5):611-21.

[2]. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016 May;150(5):1147-1159.

[3]. The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects. Diab Vasc Dis Res. 2014 Nov;11(6):440-7.

[4]. Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH. Pharmacol Res. 2019 Jun:144:377-389.

Elafibranor (code name GFT505) is a multimodal and pluripotent medication for treatment of atherogenic dyslipidemia for an overweight patient with or without diabetes. It is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. As of February 2016, elafibranor has completed 8 clinical trials and a phase III is in progress.
Elafibranor is an orally available peroxisome proliferator-activated receptor agonist that is used in combination with ursodeoxycholic acid to treat primary biliary cholangitis. Elafibranor therapy is associated with rare instances of worsening of liver enzymes during therapy but has not been convincingly linked to episodes of clinically apparent liver injury with jaundice.

---

Drug Indication
Investigated for use/treatment in atherosclerosis and diabetes mellitus type 2.
Treatment of primary biliary cholangitis
Treatment of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH)

---

Mechanism of Action
GFT505 is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. It has a sophisticated mechanism of action. It is able to differentially recruit cofactors to the nuclear receptor, which subsequently lead to differential regulation of genes and biological effect. Therefore, the ability to identify and profile the activity of selective nuclear receptor modulator (SNuRMs) is a powerful approach to select innovative drug candidates with improved efficacy and diminished side effects. These pluripotent and multimodal molecules have significant positive effects on obesity, insulin-resistance and diabetes, atherosclerosis, inflammation, and the lipid triad (increasing of HDL cholesterol, lowering of triglycerides and LDL cholesterol).

---

Introduction: The fibrates have been used for many years to treat dyslipidemias and have also recently been shown to have anti-inflammatory effects. They are relatively weak PPAR-α agonists and do have some adverse effects. Novel compounds are in development, which are selective PPAR modulators (SPPARMs) and have more potent PPAR-α agonist activity. These may prove to have advantages in the treatment of dyslipidemia, insulin resistance and non-alcoholic fatty liver disease (NAFLD). Areas covered: This review focuses on PPAR-α agonists or SPPARMs in development describing the preclinical and early clinical studies. The information was obtained by searching the published literature and abstracts from recent meetings. Ongoing clinical trials were identified using the Clinicaltrial.gov database. Expert opinion: There is still a need for new drugs to treat atherogenic dyslipidemia. The highly potent and selective PPAR-α agonist K-877 has shown beneficial effects on atherogenic dyslipidemia and absence of some adverse effects seen with fibrates. The dual PPAR-α/PPAR-δ agonist GFT-505 has shown favorable results in improving atherogenic dyslipidemia and insulin resistance and appears to be a potential candidate for the treatment of NAFLD. Long-term trials are needed to assess the safety and efficacy of these new agents for cardiovascular and liver outcomes.[1]

---

Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with concomitant hepatic inflammation. Despite its pandemic proportions, no anti-NASH drugs have been approved yet. This is partially because drug development is decelerated due to the lack of adequate tools to assess the efficacy of potential new drug candidates. The present study describes the development and application of a new preclinical model for NASH using hepatic cells generated from human skin-derived precursors. Exposure of these cells to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1β, TNF-α, TGF-β) resulted in a characteristic NASH response, as indicated by intracellular lipid accumulation, modulation of NASH-specific gene expression, increased caspase-3/7 activity and the expression and/or secretion of inflammatory markers, including CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL1a, IL6 and IL11. The human relevance of the proposed NASH model was verified by transcriptomics analyses that revealed commonly modulated genes and the identification of the same gene classes between the in vitro system and patients suffering from NASH. The application potential of this in vitro model was demonstrated by testing elafibranor, a promising anti-NASH compound currently under clinical phase III trial evaluation. Elafibranor attenuated in vitro key features of NASH, and dramatically lowered lipid load as well as the expression and secretion of inflammatory chemokines, which in vivo are responsible for the recruitment of immune cells. This reduction in inflammatory response was NFκB-mediated. In summary, this human-relevant, in vitro system proved to be a sensitive testing tool for the investigation of novel anti-NASH compounds.[4]

C22H24O4S

384.49

384.139

C, 68.73; H, 6.29; O, 16.64; S, 8.34

923978-27-2

824932-88-9; 923978-27-2;

9864881

Light yellow to yellow solid powder

1.2±0.1 g/cm3

569.0±50.0 °C at 760 mmHg

297.9±30.1 °C

0.0±1.6 mmHg at 25°C

1.606

5.63

88.9

1

5

7

27

537

0

O(C1C(C)=CC(/C=C/C(C2C=CC(SC)=CC=2)=O)=CC=1C)C(C)(C)C(=O)O

AFLFKFHDSCQHOL-IZZDOVSWSA-N

InChI=1S/C22H24O4S/c1-14-12-16(13-15(2)20(14)26-22(3,4)21(24)25)6-11-19(23)17-7-9-18(27-5)10-8-17/h6-13H,1-5H3,(H,24,25)/b11-6+

2-[2,6-dimethyl-4-[(E)-3-(4-methylsulfanylphenyl)-3-oxoprop-1-enyl]phenoxy]-2-methylpropanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 2.87 mg/mL (7.46 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.17 mg/mL (5.64 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.17 mg/mL (5.64 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 21.7 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 4 中的溶解度: ≥ 2.17 mg/mL (5.64 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 21.7 mg/mL澄清DMSO储备液加入900 μL玉米油中，混合均匀。

---

配方 5 中的溶解度: ≥ 2.17 mg/mL (5.64 mM)(饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加),澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 21.7 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。