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]。