生物活性

WY-14643 is a selective PPARα agonist (EC50 values are 0.63, 32 and > 100 μM at PPARα, PPARγ and PPARδ respectively). WY-14643 has been shown to inhibit TNF-α-induced VCAM-1, and reduce TNF-α and IL-1β. Studies indicate that WY 14643 inhibits proliferation of trophoblast cells at lower concentrations than clofibric acid, and decreases the levels of S-100 β chain (S100B) protein.

Cellviability[1]

Biologicalactivity of WY-14643

mPGES-1: microsomal prostaglandin E2synthase-1, 5-LO: 5-lipoxygenase.

体外研究

体内研究

激酶实验

细胞实验

CellCulture and Transfection[4]

Synovial fibroblasts were obtained. Synovialtissues were cut into small pieces and placed in 10-cm dishes and incubated inDMEM/F-12 medium containing 10 % FBS, 100 U/mL penicillinG, 100 mg/mLstreptomycin, and 250 ng/mL fungizone at 37 °C in a humidified 5 % CO2atmosphere. When the cultures reached confluence, cells were digested with 0.05% (w/v) trypsin/0.53 mM EDTA for 5 min at 37 °C and diluted with DMEM/F-12containing 10 % FBS to a concentration of 2 × 10× 10×10 ×10 ×10 cells/mL. Culturemedium was changed every 3 days. Experiments were performed using cells frompassages 4 to 5.

WesternBlot

After stimulation, synovial fibroblastswere harvested and lysed in 1× RIPA containing phosphatase and proteaseinhibitors. The protein concentration was measured by BCA protein assay reagentobtained from Pierce, and 30 μg of protein samples were separated by 8 or 10 % SDS-polyacrylamidegel and transferred to nitrocellulose membranes by electroblotting. Then, themembranes were blocked with 5 % nonfat milk, followed by incubation with theprimary antibody against PPAR-α, p-IkB, t-IkB, NF-kB-P50, NFkB-P65, and β-actinat 4 °C overnight. The blots were then re-probed with horseradishperoxidase-conjugated second antibodies. The protein bands were detected by theenhanced chemiluminescence reagent and examined by imaging systems. All theantibodies were purchased from Cell Signaling Technology. Protein levels wereanalyzed in comparison toβ-actin foreach group by densitometry. Experiments were independently repeated threetimes.

动物实验

Animal Studies with the PPARα Ligand WY-14643[5]

Animals were provided with food and waterad libitum and maintained under controlled temperature (23°C) and lighting(12-h light/12-h dark cycles). Mice were pooled in groups of three for eachtreatment. WY-14643 was dissolved in DMSO-corn oil (50:50) at a concentrationof 8 mg/ml. Wild-type (WT) and Tg-UGT1 mice were administered100μlof WY-14643 (40 mg/kg) by the oral route once a day for 3 days. Mice weresacrificed 24 h after the last dose, and the organs were collected and storedat -80 °C until RNA and microsomal protein could be prepared. For plasma 24G-LCAanalysis, mice were anesthetized by isoflurane inhalation 24 h after the lastdose of WY-14643, and blood was collected by cardiac puncture into heparinizedtubes. The formation of glucuronide conjugates was quantified by liquidchromatography/electrospray ionization-tandem mass spectrometry.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Michaelis M1 RF, Wurglics M, Aniceto N, Dittrich M, Zettl H, Wiese M, Wass M, Ghafourian T, Schubert-Zsilavecz M, Cinatl J. Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport. Oncotarget. . 2016 7(10):11664-11676.
[2] Popescu L, Rau O, Bottcher J, Syha Y, Schubert-Zsilavecz M. Quinoline-based derivatives of pirinixic acid as dual PPAR alpha/gamma agonists. Arch Pharm (Weinheim). 2007;340(7):367-371.
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体内溶解度

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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