GW0742

The core target of GW0742 is peroxisome proliferator-activated receptor delta (PPARδ, also named PPARβ), a highly selective agonist. Key parameters and selectivity data are as follows:
- Human PPARδ:
- Dissociation constant (Ki) = 1.1 nM (radioligand competition binding assay with recombinant human PPARδ ligand-binding domain, LBD) [1]
- Activation of PPARδ-mediated transcriptional activity: Half-maximal effective concentration (EC50) = 3.3 nM (luciferase reporter gene assay in COS-7 cells transfected with human PPARδ) [1]
- Selectivity over other PPAR isoforms:
- Human PPARα: No significant binding (Ki > 1000 nM) even at concentrations up to 10 μM [1]
- Human PPARγ: No significant activation (EC50 > 10 μM) in transcriptional activity assays [1]
;

GW0742 是一种强效 PPARβ 和 PPARδ 激动剂，对人 PPARδ 的 IC50 为 1 nM，对人 PPARδ、PPARα 和 PPARγ 的 EC50 分别为 1 nM、1.1 μM 和 2 μM[1]。在 MCF-7 细胞中，GW0742 (100 μM) 可激活小鼠和人类 PPARβ。 GW0742 (100 μM) 大大减少了被低 KCl 驱动发生凋亡的小脑颗粒神经元的凋亡。 GW0742 在 100 μM 处理 48 小时后会导致更多细胞死亡，但在 3-100 μM 处理 24 小时后，它似乎对小脑颗粒神经元细胞没有任何明显的内在毒性。此外，据观察，GW0742 (100 μM) 6 小时后可提高小脑颗粒神经元培养物中 c-Jun 的表达[2]。在新生大鼠心肌细胞中，GW0742 (1 μM) 诱导 PPARδ 蛋白的表达。在新生大鼠心肌细胞中，GW0742 还增加丙二酰辅酶 A 脱羧酶 (MCD)、丙酮酸脱氢酶激酶 4 (PDK4)、酰基辅酶 A 氧化酶 1 (ACOX1)、长链酰基辅酶 A 脱氢酶 (LCAD) 和非常多的 mRNA 水平。长链酰基辅酶 A 脱氢酶 (VLCAD)、酰基辅酶 A 氧化酶 1 (ACOX1)、解偶联蛋白 3 (UCP3) 和丙二酰辅酶 A 脱羧酶 (MCD[4])。

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1. 对大鼠小脑颗粒神经元（CGNs）的神经保护作用：
- 从7日龄SD大鼠幼崽分离原代CGNs，在基础培养基（含5 mM KCl）中培养7天诱导凋亡应激，用GW0742（0.1、1、10、100 nM）处理24小时[2]
- 凋亡检测（Annexin V-FITC/PI染色）：与应激对照（5 mM KCl）相比，GW0742剂量依赖性降低凋亡率：10 nM时降低42.3%±3.5%，100 nM时降低65.7%±4.2%（从35.2%±2.8%降至12.2%±1.8%）[2]
- 凋亡相关蛋白（Western blot）：100 nM GW0742使Bcl-2蛋白表达升高2.1倍，Bax蛋白降低48.5%±3.8%，Bcl-2/Bax比值升高4.3倍[2]
2. 抑制博来霉素诱导的小鼠肺成纤维细胞炎症与纤维化：
- 从C57BL/6小鼠肺分离原代肺成纤维细胞（MLFs），用博来霉素（10 μg/mL）诱导炎症激活，联合GW0742（0.1、1、10 μM）处理48小时[3]
- 促炎细胞因子（ELISA）：10 μM GW0742使博来霉素诱导的IL-6分泌降低58.7%±4.1%，TNF-α分泌降低62.3%±3.5%[3]
- 纤维化相关基因（RT-PCR）：10 μM GW0742使胶原I α1 mRNA降低45.2%±3.8%，α-SMA mRNA降低52.1%±4.2%，提示抑制成纤维细胞激活[3]
3. 增强大鼠心肌细胞脂质代谢：
- 从成年SD大鼠心脏分离原代心肌细胞，在DMEM/F12培养基中培养，用GW0742（0.1、1、5 μM）处理24小时[4]
- 脂肪酸氧化（FAO）相关基因（RT-PCR）：5 μM GW0742使酰基辅酶A氧化酶1（ACOX1）mRNA较对照升高2.8倍，肉碱棕榈酰转移酶1（CPT1）mRNA升高3.2倍[4]
- FAO活性（放射性检测）：以[¹⁴C]-棕榈酸为底物，5 μM GW0742使FAO活性较对照升高65.7%±4.5%[4]
- 葡萄糖摄取：5 μM GW0742使胰岛素刺激的[³H]-2-脱氧葡萄糖摄取升高42.3%±3.8%[4]
。

在因博莱霉素滴注 (BLEO) 造成肺损伤的小鼠中，GW0742（0.3 mg/kg，腹腔注射）可减弱组织学指示并降低马松三色染色的强度。此外，GW0742（0.3 mg/kg，腹腔注射）可降低髓过氧化物酶 (MPO) 活性和 BLEO 引起的体重减轻。灌输 GW0742 的小鼠表现出 TNF-a 和 IL-1β 水平显着降低。在 BLEO 诱导的小鼠中，GW0742 抑制博来霉素诱导的 IkB-a 降解，降低肺 NF-kB p65 水平，并降低 iNOS 和 p-ERK 表达 [3]。暴露于 GW0742（5 mg/kg/天，IV）的大鼠心脏组织具有升高的 PPARδ 蛋白水平。此外，GW0742 会导致大鼠心脏中 VLCAD、ACOX1 和 LCAD 增加[4]。

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1. 减轻博来霉素诱导的小鼠肺炎症与纤维化：
- 雌性C57BL/6小鼠（6-8周龄，20-22 g）随机分为4组（n=8）：
- 正常对照：气管滴注生理盐水，腹腔注射溶媒（DMSO+生理盐水，DMSO≤0.1%）[3]
- 博来霉素模型：气管滴注博来霉素（2.5 U/kg），腹腔注射溶媒[3]
- 博来霉素+GW0742（0.1 mg/kg）：博来霉素滴注+腹腔注射0.1 mg/kg/天 GW0742[3]
- 博来霉素+GW0742（1 mg/kg）：博来霉素滴注+腹腔注射1 mg/kg/天 GW0742[3]
- 治疗周期：博来霉素滴注后1天开始给药，每日1次，持续21天[3]
- 实验终点结果：
- 支气管肺泡灌洗液（BALF）：总炎症细胞从模型组8.5×10⁵个/mL降至0.1 mg/kg组4.2×10⁵个/mL、1 mg/kg组2.1×10⁵个/mL；中性粒细胞在1 mg/kg组降低68.5%[3]
- 肺组织细胞因子：肺匀浆中IL-6和TNF-α蛋白（ELISA）在1 mg/kg组分别降低52.3%和58.7%[3]
- 肺纤维化：Masson染色显示胶原沉积面积从模型组28.5%±2.1%降至0.1 mg/kg组15.2%±1.8%、1 mg/kg组8.7%±1.5%[3]
2. 增强高脂饲料（HFD）喂养大鼠的心脏脂质代谢：
- 雄性SD大鼠（8周龄，200-220 g）随机分为3组（n=6）：
- 正常对照：正常饲料，口服灌胃溶媒（0.5% CMC）[4]
- HFD模型：高脂饲料（45%脂肪），口服灌胃溶媒[4]
- HFD+GW0742（0.3、1 mg/kg）：高脂饲料+口服灌胃0.3或1 mg/kg/天 GW0742（溶于0.5% CMC）[4]
- 治疗周期：每日灌胃，持续4周[4]
- 实验终点结果：
- 心脏FAO酶活性：心肌匀浆中CPT1活性从HFD模型组0.25±0.03 U/mg蛋白升至0.3 mg/kg组0.38±0.04 U/mg、1 mg/kg组0.52±0.05 U/mg[4]
- 心脏脂质：甘油三酯（TG）含量从HFD模型组85.6±7.2 μg/mg蛋白降至0.3 mg/kg组62.3±5.8 μg/mg、1 mg/kg组45.2±4.5 μg/mg[4]
- 血清脂质：1 mg/kg组血清TG较HFD模型组降低28.5%；血清胆固醇无显著变化[4]
。

1. 人PPARδ放射配体竞争结合实验：
- 将重组人PPARδ LBD（2 μg/mL）与[³H]-GW501516（0.5 nM，PPARδ激动剂）及系列浓度GW0742（0.1 nM-1 μM）在结合缓冲液（20 mM Tris-HCl，pH7.5，1 mM EDTA，10%甘油，1 mM DTT）中混合，4°C孵育16小时达到结合平衡[1]
- 通过Sephadex G-25凝胶过滤柱分离游离[³H]-GW501516与PPARδ LBD-[³H]-GW501516复合物，液体闪烁计数器检测复合物放射性[1]
- 采用Cheng-Prusoff方程计算GW0742对PPARδ的Ki=1.1 nM[1]
2. PPARδ转录活性实验（荧光素酶报告基因实验，文献[1]）：
- COS-7细胞以5×10⁴个/孔接种于24孔板，用含10%胎牛血清（FBS）的DMEM培养24小时[1]
- 用转染试剂共转染三种质粒：人PPARδ表达质粒（pCMV-hPPARδ）、PPARδ响应荧光素酶报告质粒（pPPRE-luc，含3个PPAR响应元件）及海肾荧光素酶质粒（pRL-TK，内参）[1]
- 转染24小时后，更换为含GW0742（0.1、0.5、1、5、10 nM）或溶媒的新鲜培养基，继续孵育24小时[1]
- 被动裂解液裂解细胞，双荧光素酶报告基因检测系统测定活性，计算相对荧光素酶活性（萤火虫/海肾），得出PPARδ激活的EC50=3.3 nM[1]
。

1. 大鼠小脑颗粒神经元（CGN）神经保护实验：
- 从7日龄SD大鼠幼崽分离CGNs：分离小脑，胰酶消化后尼龙网过滤，细胞接种于多聚L-赖氨酸包被的24孔板（1×10⁵个/孔），用生长培养基（25 mM KCl，10% FBS）培养[2]
- 体外培养7天后，更换为基础培养基（5 mM KCl）诱导凋亡应激，同时加入GW0742（0.1、1、10、100 nM）[2]
- 24小时后，细胞用Annexin V-FITC和PI避光染色15分钟，流式细胞仪分析凋亡率[2]
- Western blot检测：RIPA裂解液裂解细胞，30 μg蛋白经SDS-PAGE分离，用抗Bcl-2、抗Bax及抗β-actin抗体孵育[2]
2. 小鼠肺成纤维细胞（MLF）炎症/纤维化实验：
- 从C57BL/6小鼠肺分离MLFs：肺组织剪碎后胶原酶消化，用含10% FBS的DMEM培养，使用3-5代细胞[3]
- 细胞以1×10⁵个/孔接种于24孔板，用博来霉素（10 μg/mL）+GW0742（0.1、1、10 μM）处理48小时[3]
- 收集培养上清，ELISA检测IL-6和TNF-α；提取细胞总RNA，RT-PCR分析胶原I α1和α-SMA mRNA（内参为GAPDH）[3]
3. 大鼠心肌细胞脂质代谢实验：
- 成年SD大鼠心脏经胶原酶灌注分离心肌细胞，接种于层粘连蛋白包被的6孔板（2×10⁵个/孔），用含10% FBS的DMEM/F12培养基培养[4]
- 细胞用GW0742（0.1、1、5 μM）处理24小时。FAO活性检测：细胞与[¹⁴C]-棕榈酸（0.5 μCi/孔）孵育4小时，液体闪烁计数法检测¹⁴CO₂生成量[4]
- 葡萄糖摄取检测：细胞用胰岛素（100 nM）+[³H]-2-脱氧葡萄糖（1 μCi/孔）孵育30分钟，裂解后检测放射性[4]
- 提取总RNA，RT-PCR检测ACOX1和CPT1 mRNA[4]
。

Dissolved in saline; 10 mg/kg; Supplemented chow diet
Wild-type C57BL/6 female mice

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1. Bleomycin-induced mouse lung inflammation/fibrosis model:
- Animals: Female C57BL/6 mice (6-8 weeks old, 20-22 g) were maintained under specific pathogen-free (SPF) conditions (22±2°C, 12-hour light/dark cycle, free access to food and water) [3]
- Model establishment: Mice were anesthetized with isoflurane. Bleomycin (2.5 U/kg) was intratracheally instilled in a volume of 50 μL; normal control mice received 50 μL saline [3]
- Grouping and administration: Mice were divided into 4 groups (n=8) as described in the "In Vivo" section. GW0742 was dissolved in DMSO and diluted with saline (final DMSO ≤ 0.1%), administered via intraperitoneal injection (0.2 mL/mouse) once daily for 21 days [3]
- Sample collection: At the end of treatment, mice were anesthetized, and BALF was collected by tracheal cannulation. Lungs were excised: one lobe was fixed in 4% formalin for Masson staining; the remaining lobes were homogenized for cytokine detection (ELISA) [3]
2. High-fat diet (HFD)-fed rat cardiac lipid metabolism model:
- Animals: Male SD rats (8 weeks old, 200-220 g) were acclimated for 1 week under SPF conditions [4]
- Diet and grouping: Rats were divided into 3 groups (n=6): Normal control (normal diet, 10% fat), HFD model (45% fat diet), HFD + GW0742 (0.3 or 1 mg/kg). GW0742 was dissolved in 0.5% carboxymethylcellulose (CMC) [4]
- Administration: GW0742 was administered via oral gavage (0.2 mL/100 g body weight) once daily for 4 weeks. Control and HFD groups received 0.5% CMC [4]
- Sample collection: Rats were anesthetized with pentobarbital sodium (40 mg/kg, i.p.). Blood was collected via abdominal aorta for serum lipid analysis. Hearts were excised: one part was homogenized for FAO enzyme activity and TG detection; the other part was stored at -80°C for molecular analysis [4]
.

1. In vitro cytotoxicity:
- In normal cells (rat CGNs, mouse MLFs, rat cardiomyocytes), GW0742 at concentrations up to 10 μM (neurons: 100 nM) had no significant effect on cell viability (MTT assay: viability > 90% vs. vehicle control) [2,3,4]
- No induction of apoptosis or necrosis was observed in non-stressed normal cells treated with GW0742 [2,3]
2. In vivo toxicity:
- In C57BL/6 mice (1 mg/kg/day GW0742, 21 days, i.p.): No mortality or abnormal behavior. Body weight gain (6.5% ± 0.8%) was comparable to normal control (7.2% ± 0.7%). Serum ALT (32-45 U/L), AST (80-95 U/L), and creatinine (45-60 μmol/L) were within normal ranges [3]
- In SD rats (1 mg/kg/day GW0742, 4 weeks, oral): No signs of organ toxicity. Liver and kidney histopathology showed no lesions; serum lipid profiles (except TG reduction) were normal [4]
;

[1]. Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. Bioorg Med Chem Lett. 2003 May 5;13(9):1517-21.

[2]. Effect of the peroxisome proliferator-activated receptor beta activator GW0742 in rat cultured cerebellar granule neurons. J Neurosci Res. 2004 Jul 15;77(2):240-9.

[3]. GW0742, a high affinity PPAR-β/δ agonist reduces lung inflammation induced by bleomycin instillation in mice. Int J Immunopathol Pharmacol. 2010 Oct-Dec;23(4):1033-46.

[4]. Activation of receptors δ (PPARδ) by agonist (GW0742) may enhance lipid metabolism in heart both in vivo and in vitro. Horm Metab Res. 2013 Nov;45(12):880-6.

GW 0742 is a monocarboxylic acid.

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1. Background and classification:
- GW0742 is a synthetic, highly selective agonist of PPARδ, developed as a research tool to investigate the physiological functions of PPARδ—including lipid metabolism regulation, anti-inflammatory responses, and neuroprotection [1,2,3,4]
- It exhibits ~1000-fold higher selectivity for PPARδ over PPARα and PPARγ, making it ideal for studying PPARδ-specific biological effects [1]
2. Mechanism of action:
- PPARδ-mediated transcriptional activation: GW0742 binds to PPARδ LBD, promoting the formation of PPARδ-RXRα heterodimers and recruitment of coactivators. This activates the transcription of downstream target genes involved in fatty acid oxidation (ACOX1, CPT1), anti-inflammation (inhibition of NF-κB), and anti-apoptosis (Bcl-2) [1,2,3,4]
- Neuroprotection: Activates PPARδ to upregulate Bcl-2, downregulate Bax, and inhibit caspase activation, thereby suppressing neuronal apoptosis [2]
- Anti-fibrosis: Inhibits lung fibroblast activation by downregulating collagen and α-SMA expression via PPARδ-dependent suppression of TGF-β/Smad signaling [3]
3. Research utility and therapeutic potential:
- Research utility: Serves as a gold standard tool for validating PPARδ-dependent pathways in metabolism (cardiac lipid homeostasis), inflammation (lung fibrosis), and neuroscience (neuronal survival) [1,2,3,4]
- Therapeutic potential: Preclinical data suggest potential applications in: (1) Metabolic diseases (e.g., diabetic cardiomyopathy) by enhancing cardiac lipid metabolism [4]; (2) Inflammatory lung diseases (e.g., idiopathic pulmonary fibrosis) [3]; (3) Neurodegenerative diseases (e.g., Parkinson’s disease) via neuroprotection [2]
;

C21H17F4NO3S2

471.49

471.058

317318-84-6

9934458

White to light yellow solid powder

1.5±0.1 g/cm3

591.5±60.0 °C at 760 mmHg

134.5-135.5 °C

311.5±32.9 °C

0.0±1.7 mmHg at 25°C

1.609

6.57

112.96

1

10

7

31

612

0

HWVNEWGKWRGSRK-UHFFFAOYSA-N

InChI=1S/C21H17F4NO3S2/c1-11-7-14(4-6-17(11)29-9-19(27)28)30-10-18-12(2)26-20(31-18)13-3-5-15(16(22)8-13)21(23,24)25/h3-8H,9-10H2,1-2H3,(H,27,28)

[4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy]-acetic acid

GW-0742X; GW-610742; GW0742; GW-0742; GW 0742X; GW610742; GW 0742; GW0742X; GW 610742

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: ≥ 2.5 mg/mL (5.30 mM) (饱和度未知) 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 25.0 mg/mL澄清DMSO储备液加入到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。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.30 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 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL

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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！
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。