WY-14643 (Pirinixic Acid)
(Synonyms: 匹立尼酸,WY 14643,WY14643) 目录号 : GC14403
WY-14643 (Pirinixic Acid)是一种高效、具备选择性高亲和力的过氧化物酶体增殖物激活受体α（PPARα）受体激动剂，对小鼠的 PPARα受体的EC50为0.63μM，对人的 PPARα受体的EC50为5μM。
Cas No.:50892-23-4
Sample solution is provided at 25 µL, 10mM.
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WY-14643 (Pirinixic Acid) is a highly potent and selective agonist of the peroxisome proliferator-activated receptor alpha(PPARα), exhibiting an EC50 of 0.63μM for mouse PPARα receptors and an EC50 of 5μM for human PPARα receptors[1].PPARα is a ligand-activated transcription factor that plays a crucial role in lipid metabolism across various tissues and is associated with several diseases, including metabolic syndrome, Alzheimer’s disease, and cardiovascular diseases[2]. WY-14643 (Pirinixic Acid) is a potent antihypercholesterolemic agent that interacts with the PPARα receptor, inducing conformational changes that facilitate heterodimerization with the retinoid X receptor (RXR). This heterodimer then binds to specific response elements in target gene promoters, leading to the activation of transcription[3,4].
Treatment of MCF-7 cells with WY-14643 (30–300μM) led to an increased expression of human cytochrome P450 1B1 (CYP1B1) protein compared to the untreated group, which is implicated in the initiation and progression of breast cancer[5]. Treatment of TCL-1 cells with WY-14643 (0.05–0.2mM) significantly enhanced the activity of catalase (catalase) and increased progesterone secretion at low concentrations, while treatment with higher concentrations reduced the secretion of human chorionic gonadotropin (hCG) and suppressed cell proliferation, suggesting that WY-14643 can modulate trophoblast cell metabolism and function[6].
WY-14643 (5mg/kg or 10mg/kg, 7d) administered via intraperitoneal injection was able to reduce lipopolysaccharide (LPS)-induced depressive-like behaviors in mice and improve anhedonia, demonstrating its potential as an effective antidepressant[7]. WY-14643 (60mg/kg, 30min) administered via intraperitoneal injection prior to traumatic brain injury (TBI) significantly decreased brain water content in mice, alleviating cerebral edema. These results suggest that WY-14643 has a protective effect on blood-brain barrier function following TBI[8].
References:
[1] Willson T M, Brown P J, Sternbach D D, et al., The PPARs: From Orphan Receptors to Drug Discovery, Journal of Medicinal Chemistry[J]. 2000, 43: 527-550.
[2] Lin Y, Wang Y, Li P F, PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases, Front Endocrinol (Lausanne)[J]. 2022, 13: 1074911.
[3] Santilli A A, Scotese A C, Tomarelli R M, A potent antihypercholesterolemic agent: [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14643), Experientia[J]. 1974, 30: 1110-1111
[4] Forman B M, Chen J, Evans R M, Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta, Proc Natl Acad Sci U S A[J]. 1997, 94: 4312-4317.
[5] Hwang Y P, Won S S, Jin S W, et al., WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells, Int J Mol Sci[J]. 2019, 20: 5928.
[6] Hashimoto F, Morita M, Iwasaki K, et al., Effects of WY-14643 on Peroxisomal Enzyme Activity and Hormone Secretion in Immortalized Human Trophoblast Cells, Biological and Pharmaceutical Bulletin[J]. 2009, 32: 1278-1282.
[7] Yang R, Wang P, Chen Z, et al., WY-14643, a selective agonist of peroxisome proliferator-activated receptor-α, ameliorates lipopolysaccharide-induced depressive-like behaviors by preventing neuroinflammation and oxido-nitrosative stress in mice, Pharmacol Biochem Behav[J]. 2017, 153: 97-104.
[8] Neuhaus W, Krämer T, Neuhoff A, et al., Multifaceted Mechanisms of WY-14643 to Stabilize the Blood-Brain Barrier in a Model of Traumatic Brain Injury, Frontiers in Molecular Neuroscience[J]. 2017, 10: 149.
WY-14643 (Pirinixic Acid)是一种高效、具备选择性高亲和力的过氧化物酶体增殖物激活受体α（PPARα）受体激动剂，对小鼠的 PPARα受体的EC50为0.63μM，对人的 PPARα受体的EC50为5μM[1]。PPARα（过氧化物酶体增殖物激活受体α）是一种配体激活的转录因子，主要参与多种组织的脂质代谢，与代谢综合症、阿尔茨海默病和心血管疾病等多种疾病相关[2]。WY-14643 (Pirinixic Acid)是一种有效的抗高胆固醇药，能够和PPARα受体结合，诱导受体构象变化，使其能够和9-顺式视黄酸受体（RXR）形成异二聚体，结合到对应的靶基因上，促进靶基因的转录[3,4]。
WY-14643（30-300μM）处理MCF-7细胞，和未处理组相比，细胞中人类细胞色素P450 1B1（CYP1B1）蛋白的表达增加，影响乳腺癌的发生和发展[5]。WY-14643（0.05-0.2 mM）处理TCL-1细胞，与未处理组相比，低浓度的WY-14643处理下，细胞中过氧化氢酶（catalase）活性显著增加，孕酮分泌增加，高浓度WY-14643处理下，人绒毛膜促性腺激素（hCG）分泌减少，细胞增殖减少，这说明WY-14643能够影响滋养层细胞的代谢和功能[6]。
WY-14643（5mg/kg or 10mg/kg, 7d）通过腹腔注射的方式对小鼠进行处理，能够减少脂多糖（LPS）诱导的小鼠的抑郁样行为，改善快感，展现出其作为潜在抗抑郁药的有效性[7]。WY-14643（60mg/kg, 30min）通过腹腔注射的方式对小鼠进行预处理，能够显著减少创伤性脑损伤（TBI）后小鼠脑水分含量的增加，减轻水肿的形成，这说明WY-14643对血脑屏障功能具有保护作用[8]。
| 细胞实验 [1]: | |
实验细胞系 | MCF-7 cells |
实验方案 | MCF-7 cells were seeded at a density of 4×104 cells per 500μL in 48-well plates. After incubation for 24h, the growth medium was replaced with serum-free medium and the cells were treated with WY-14643 (30–300μM) or an equal volume of dimethyl sulfoxide for 24h at 37℃. Culture supernatants were subjected to analysis using the lactate dehydrogenase assay and the absorbance at 490nm was measured using a microplate reader. Cell viability was determined using the MTT assay.After treatment, MCF-7 cells were lysed in lysis buffer (120mM NaCl, 40mM Tris[pH 8.0], and 0.1% nonidet P-40) on ice for 30min and centrifuged at 12,000rpm for 20min. Supernatants were collected and protein concentrations were measured using a protein assay kit. Aliquots of the lysates (50μg protein) were boiled for 5min andresolved by using 10% sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The proteins were transferred to polyvinylidene difluoride membranes and incubated with the appropriate primary antibodies. The membranes were incubated with the secondary anti-mouse or anti-rabbit antibody. Finally, the protein bands were detected using an enhanced chemiluminescence western blotting detection kit. |
反应条件 | 30–300μM; 24h |
实验结果 | WY-14643 enhances the expression of CYP1B1 through a PPARα-dependent mechanism. |
| 动物实验 [2]: | |
动物模型 | Traumatic brain injury (TBI) mice |
实验方案 | WY-14643(60mg/kg, i.p.) or vehicle was administered 30min before Controlled Cortical Impact (CCI). Male C57Bl6/N mice were anesthetized with 5mg/kg midazolam, 0.05mg/kg fentanyl, and 0.5mg/kg medetomidine intraperitoneally. Rectal temperature was maintained at 37℃ with a thermostatically regulated, feedback-controlled heating pad. The cranium was fixed in a stereotactical frame, a craniotomy was generated between lambdoid, sagittal and coronal sutures with a saline cooled high speed drill. The trauma was induced with an electromagnetic cortical impact device diameter of the impactor tip: 3mm; impact velocity: 6m/sec; impact duration: 200ms, and displacement: 1.5mm. The craniotomy was closed with the initially removed bone flap using conventional tissue glue. The skin was carefully closed with four single button sutures, anaesthesia antagonized (0.5mg/kg Flumazenil, and 2.5mg/kg Atipamezole hydrochloride, i.p.) and the animals were transferred back into their cages. The animals were placed for 1.5h in a neonatal incubator with controlled air temperature (35℃) and ambient humidity (35%) to maintain constant body temperature and avoid hypothermia. The animals were reanaesthetized and killed by cervical dislocation. For the quantification of brain water content and further investigations the cerebellum was separated and the |
剂型 | 60mg/kg for 30min; i.p. |
实验结果 | Treatment of WY-14643 significantly protected against radiocontrast nephropathy. |
References: | |
| Cas No. | 50892-23-4 | SDF | |
| 别名 | 匹立尼酸,WY 14643,WY14643 | ||
| 化学名 | 2-[4-chloro-6-(2,3-dimethylanilino)pyrimidin-2-yl]sulfanylacetic acid | ||
| Canonical SMILES | CC1=C(C(=CC=C1)NC2=CC(=NC(=N2)SCC(=O)O)Cl)C | ||
| 分子式 | C14H14ClN3O2S | 分子量 | 323.8 |
| 溶解度 | ≥ 16.2 mg/mL in DMSO, ≥ 48.8 mg/mL in EtOH with ultrasonic | 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 | 3.0883 mL | 15.4416 mL | 30.8833 mL |
| 5 mM | 0.6177 mL | 3.0883 mL | 6.1767 mL |
| 10 mM | 0.3088 mL | 1.5442 mL | 3.0883 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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