Wy-14643 is a selective PPARα agonist with EC50 values of 5μM and 0.63μM for human and murine PPARα, also exhibited less potency to human PPARγ/δwith IC50 values of 60 and 35μM, respectively, and murine PPARγ with IC50 value of 32μM in cell-based transactivation assays. Wy-14643 has been developed as hypolipidemic agents through optimization of their lipid-lowering activity in rodents[1]. Wy-14643 induced expression of UCP3 in rat neonates[2]. Oral administration of Wy-14643 0.1% in diet for 10 days in high-fat-diet mice or chow-fed foz/foz mice reduced steatosis in nonalcoholic steatohepatitis and simple steatosis livers and fewer inflammatory foci, with hepatoprotection against ischemia–reperfusion injury by alanine aminotransferase release. The reduction of hepatic VCAM-1 and ICAM-1 expression, IL-1α, TNF-α, IL-12 and activated NF-κB, p38, IL-6 production and cell cycle entry observed[4].
Induced the expression of ADAM10, increased the release of sAPPα, and reduced Aβ production
Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8445-50.
HEK293-AβPPwt cells
0.1 µM
24 hours
To evaluate the effect of MH84 on mitochondrial mass, results showed that MH84 increased mitochondrial mass in treated cells
Alzheimers Res Ther. 2018 Feb 13;10(1):18.
HEK293-AβPPsw cells
0.1 µM
24 hours
To evaluate the effect of MH84 on mitochondrial mass, results showed that MH84 increased mitochondrial mass in treated cells
Alzheimers Res Ther. 2018 Feb 13;10(1):18.
HepG2 cells
20 µM
48 hours
To study the interaction between PPARα and YAP and the nuclear translocation of YAP
Hepatology. 2022 Jan;75(1):74-88.
Mouse pulmonary microvascular endothelial cells
1 µM
48 hours
To evaluate cell proliferation, results showed that EET analogs significantly stimulated the proliferation of Cyp2c44 KO endothelial cells.
Cancer Res. 2014 Jan 15;74(2):621-31.
Pirinixic Acid/匹立尼酸 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
KRasLA2 mouse model
Drinking water
0.02% Wy-14643
Continuous administration from 1 to 3 months or 3 to 5 months
To evaluate the effect of Wyeth-14,643 on primary lung cancer growth, results showed that Wyeth-14,643 significantly reduced the number and size of lung cancer.
Cancer Res. 2014 Jan 15;74(2):621-31.
Mice
Mycfl/fl and Mycfl/fl,ERT2-Cre mice
Oral
0.1% Wy-14,643
Once daily for two weeks
To investigate the role of Myc in hepatocellular proliferation, results showed that Mycfl/fl,ERT2-Cre mice had significantly reduced hepatocellular proliferation
J Hepatol. 2014 Feb;60(2):331-8
Mice
Hepatocyte-specific Myc knockout mice (MycΔHep)
Oral
0.1% Wy-14643
Daily for two days
To investigate the amplification effect of MYC on Krt23 expression after PPARA activation, it was found that Krt23 was significantly upregulated in wild-type mice but significantly attenuated in MycΔHep mice.
Hepatology. 2019 Jul;70(1):154-167
Mice
C57BL/6J background mice
Oral
0.1% WY-14643
24 or 48 hours
To investigate the effect of PPARα activation on the expression of lncRNA Gm15441 in mouse liver and its impact on inflammasome activation. Results showed that PPARα activation significantly induced Gm15441 expression and reduced NLRP3 inflammasome activation by suppressing TXNIP expression.
Nat Commun. 2020 Nov 17;11(1):5847
Mice
Rap1-/- mice
Intraperitoneal injection
1.1 mg/kg/day
Once daily for 6 weeks
Inhibition of p53 improved cardiac fatty acid metabolism and restored cardiac function
Theranostics. 2021 Mar 4;11(10):4710-4727.
Mice
Lieber-DeCarli model
Diet
10 mg/L
Continued for 18 or 25 days
WY-14,643 enhanced ethanol metabolism and escalated ethanol clearance via a PPARα-PEX16-ACOX-catalase network.
Free Radic Biol Med. 2023 Nov 1;208:221-228
C57BL/6J mice
Chronic ethanol feeding model
Oral
10 mg/L
3 weeks
WY-14,643 ameliorates ethanol and nicotine-induced fatty liver through induction of peroxisome proliferator-activated receptor α (PPARα) pathways, but it also enhances ethanol and nicotine-induced liver injury. WY-14,643 escalates ethanol metabolism by inducing catalase.
Free Radic Biol Med. 2021 Jun;169:283-293
C57BL/6 mice
PPAR α activation-induced hepatomegaly model
Intraperitoneal injection
100 mg/kg/d
Once daily for 1, 2, 3, 5, or 10 days
To investigate PPAR α activation-induced hepatomegaly and its zonal distribution characteristics, it was found that PPAR α activation mainly caused hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area.
Acta Pharmacol Sin. 2023 Oct;44(10):2037-2047
C57BL/6 mice
Wild-type mice and PparaΔHep mice
100 mg/kg/day
Once daily for 10 days
To investigate the effect of PPARα activation on hepatomegaly and liver regeneration, results showed that PPARα activation significantly induced hepatomegaly and accelerated liver regeneration
Hepatology. 2022 Jan;75(1):74-88.
C57BL/6 mice
Thy-1 AβPPSL mouse model
Oral gavage
12 mg/kg
Once daily for 21 days
To evaluate the effect of MH84 on mitochondrial dysfunction in a mouse model of early Alzheimer's disease, results showed that MH84 improved mitochondrial function and reduced β-secretase-related C99 peptide and Aβ40 levels
Alzheimers Res Ther. 2018 Feb 13;10(1):18.
Rats
Nicotine self-administration model
Intraperitoneal injection
20 or 40 mg/kg
20 minutes before each session, for 3 consecutive days
To evaluate the effect of PPAR-α agonists on nicotine self-administration behavior, results showed that PPAR-α agonists significantly reduced nicotine self-administration.
Biol Psychiatry. 2011 Apr 1;69(7):633-41
Mice
ApoE-/- mice
Oral
5 mg/day/mice
For 4 weeks
To evaluate the effect of LP105 on aortic aneurysm development, results showed that LP105 significantly attenuated vascular remodeling and aortic aneurysm formation.
Br J Pharmacol. 2011 Aug;163(8):1721-32
Mice
ANIT-induced cholestasis model
Oral
5, 25, 125 mg/kg
Twice daily for 5 days
To evaluate the protective effect of feno?brate against ANIT-induced cholestasis and liver injury. The results showed that feno?brate exerted its protective effect by inhibiting the JNK signaling pathway, and this protection was dependent on PPARα and the dose of feno?brate.
Br J Pharmacol. 2017 Sep;174(18):3000-3017
Zebrafish embryo
Zebrafish embryo model
Water exposure
51.8 μM
96 hours
The uptake kinetics and biotransformation of Pirinixic Acid in zebrafish embryos were studied, revealing that its internal concentration was 89.7 times lower than predicted, and 6 transformation products were identified.
Environ Sci Technol. 2024 Oct 8;58(40):17898-17907
Activation of human PPARalpha ligand binding domain expressed in COS7 cells by luciferase reporter gene assay, IC50=36.3 μM
25037914
EAhy926 cells
10 uM
Function assay
12 h
Inhibition of tube formation in human EAhy926 cells at 10 uM pre-incubated for 12 hrs measured after 24 hrs by phase-contrast microscopy
19036594
HEK293 cells
Function assay
Agonist activity at human PPARalpha expressed in HEK293 cells cotransfected with PPREx4-TK-luc assessed as activation of luciferase activity measured after 48 hrs by transactivation assay, EC50=23.33 μM
23265844
Hep G2 cells
Function assay
Agonist activity at mouse PPARalpha ligand binding domain expressed in human Hep G2 cells co-transfected with Gal4-DBD by luciferase reporter gene assay, EC50=0.04 μM
19053776
HepaR cells
25 μM
Function assay
1 day
Agonist activity at PPARalpha in human HepaR cells assessed as increase in HMGCS2 gene expression at 25 uM incubated for 1 day by quantitative PCR method relative to untreated control
25497132
MCF7 cells
Function assay
Agonist activity at human PPARalpha expressed in MCF7 cells co-transfected CPTI DR1-type RE after 6 hrs by luciferase reporter gene assay, EC50=0.542 μM
24936232
mouse NIH3T3 cells
0.1-10 μM
Function assay
Transactivation of mouse recombinant PPARalpha expressed in mouse NIH3T3 cells at 0.1 uM to 10 uM by PPRE activation based dual luciferase reporter gene assay relative to control
19237283
U2OS cells
Function assay
Agonist activity at human PPARalpha in U2OS cells by transactivation assay, EC50=12 μM
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