PPARδ(Ki = 6 nM); PPARγ (Ki = 730 nM)
L-165041 targets the peroxisome proliferator-activated receptor delta (PPARδ), a nuclear receptor that regulates the expression of genes involved in lipid metabolism, glucose homeostasis, and energy balance. As a PPARδ agonist, L-165041 binds to the receptor and activates it, leading to the transcription of target genes. This results in enhanced fatty acid oxidation, improved insulin sensitivity, and modulation of metabolic processes. L-165041 is a cell-permeable compound.

PPARδ agonist L-165041 has a Ki of 6 nM for PPARδ and roughly 730 nM for PPARγ [1]. L-165041 (1 or 5 μM) prevents endothelial cell (EC) migration and rotation caused by VEGF. L-165041 has a deleterious effect on the VEGF-activated human venovenous endothelial cells' (HUVEC) cell cycle progression. PPARδ-uncoupled, VEGF-induced angiogenesis is inhibited by L-165041 (10 μM) [2]. rVSMC migration and PDGF-induced migration are inhibited by PPARδ ligand L-165041. After an hour, PDGF-induced cell migration was reduced by L-165041. Significant inhibition of PDGF-induced S phase transition is seen with 10 μM L-165041 [4].

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In vitro, L-165041 activates PPARδ in cell-based reporter assays. The compound's PPARδ agonist activity has been characterized in transfection assays using a PPAR response element (PPRE)-luciferase reporter. L-165041 enhances fatty acid oxidation in cultured cells and modulates the expression of genes involved in lipid and glucose metabolism. The compound is cell-permeable and is used to study PPARδ-mediated signaling in various cell types.

In mice, L-165041 (5 mg/kg/day, i.p.) dramatically lowers the production of lipid droplets. L-165041 dramatically lowered the mice's triglyceride levels. L-165041 went up in contrast to the vector group. mice given L-165041 treatment while the vehicle group's lipoprotein lipase (LPL) expression was significantly elevated [3].

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In vivo, L-165041 has been used in preclinical studies to investigate the role of PPARδ in metabolic disorders. By activating PPARδ, the compound enhances fatty acid oxidation, improves insulin sensitivity, and modulates energy balance. L-165041 has been studied in animal models of obesity, diabetes, and cardiovascular diseases. However, specific in vivo efficacy data are limited in the available literature, as L-165041 is primarily a research tool.

Peroxisome proliferator-activated receptor (PPAR)δ is known to be expressed ubiquitously and involved in lipid and glucose metabolism. Recent studies have demonstrated that PPARδ is expressed in endothelial cells (ECs) and plays a potential role in endothelial survival and proliferation. Although PPARα and PPARγ are well recognized to play anti-inflammatory, antiproliferative, and antiangiogenic roles in ECs, the general effect of PPARδ on angiogenesis in ECs remains unclear. Thus, we investigated the effect of the PPARδ ligand L-165041 on vascular EC proliferation and angiogenesis in vitro as well as in vivo. Our data show that L-165041 inhibited VEGF-induced cell proliferation and migration in human umbilical vein ECs (HUVECs). L-165041 also inhibited angiogenesis in the Matrigel plug assay and aortic ring assay. Flow cytometric analysis indicated that L-165041 reduced the number of ECs in the S phase and the expression levels of cell cycle regulatory proteins such as cyclin A, cyclin E, CDK2, and CDK4; phosphorylation of the retinoblastoma protein was suppressed by pretreatment with L-165041. We confirmed whether these antiangiogenic effects of L-165041 were PPARδ-dependent using GW501516 and PPARδ siRNA. GW501516 treatment did not inhibit VEGF-induced angiogenesis, and transfection of PPARδ siRNA did not reverse this antiangiogenic effect of L-165041, suggesting that the antiangiogenic effect of L-165041 on ECs is PPARδ-independent. Together, these data indicate that the PPARδ ligand L-165041 inhibits VEGF-stimulated angiogenesis by suppressing the cell cycle progression independently of PPARδ. This study highlights the therapeutic potential of L-165041 in the treatment of many disorders related to pathological angiogenesis[3].

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The non-cellular assay for L-165041 involves measuring its binding affinity for PPARδ using radioligand binding assays or its agonist activity using cell-free transcription assays. In a typical transactivation assay, a PPARδ protein is incubated with a labeled ligand, and the displacement of the ligand by L-165041 is measured. Alternatively, the compound's ability to recruit coactivator proteins to PPARδ is assessed using fluorescence resonance energy transfer (FRET) or AlphaScreen assays.

The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes (alpha, beta/delta, and gamma). PPAR delta is ubiquitously expressed and involved in lipid and glucose metabolism. However, the effect of PPAR delta on vascular smooth muscle cell (VSMC) proliferation and migration has not been fully elucidated yet. Here, we investigated the effect of L-165041, a selective ligand for PPAR delta, on PDGF-induced rat VSMC proliferation. Our data show that L-165041 inhibited rat VSMC proliferation in a dose dependent manner by blocking G(1) to S phase progression and repressing the phosphorylation of retinoblastoma protein (Rb). Furthermore, L-165041 inhibited PDGF-induced expression of cyclin D1 and CDK4. These effects less likely involve PPAR gamma pathway because PPAR gamma antagonist GW9662 pretreatment failed to reverse the inhibitory effect of L-165041 on rVSMC proliferation and migration. For in vivo studies, L-165041 was administered to Sprague-Dawley rats using osmotic pumps before and after the carotid balloon injury, and L-165041 decreased neointima formation after the carotid injury. In conclusion, our results suggest that PPAR delta ligand L-165041 can be a therapeutic agent to control pathologic cardiovascular conditions such as restenosis and atherosclerosis[4].

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The cellular assay for L-165041 involves treating cells expressing PPARδ with the compound and measuring its effects on gene expression. Cells are transfected with a PPRE-luciferase reporter plasmid and a PPARδ expression vector. L-165041 is added at various concentrations, and luciferase activity is measured after a defined incubation period. The EC50 for PPARδ activation is determined from concentration-response curves. The effects of L-165041 on the expression of PPARδ target genes (e.g., PDK4, ANGPTL4) are measured by quantitative PCR.

Although peroxisome proliferator-activated receptor delta (PPARdelta) has been implicated in energy metabolism and lipid oxidation process, detailed roles of PPARdelta in lipid homeostasis under pathologic conditions still remain controversial. Thus, we investigated the effect of PPARdelta ligand L-165041 on Western diet-induced fatty liver using low-density lipoprotein receptor-deficient (LDLR(-/-)) mice. LDLR(-/-) mice received either L-165041 (5mg/kg/day) or vehicle (0.1N NaOH) with Western diet for 16 weeks. According to our data, L-165041 drastically reduced lipid accumulation in the liver, decreasing total hepatic cholesterol and triglyceride content compared to the vehicle group. Gene expression analysis demonstrated that L-165041 lowered hepatic expression of PPARgamma, apolipoprotein B, interleukin 1 beta (IL-1beta), and interleukin-6. In contrast, L-165041 increased hepatic expressions of PPARdelta, lipoprotein lipase (LPL), and ATP-binding cassette transporter G1 (ABCG1). Our data suggest that L-165041 might be effective in preventing Western diet-induced hepatic steatosis by regulating genes involved in lipid metabolism and the inflammatory response[3].

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In the in vivo efficacy study, L-165041 is administered orally or by intraperitoneal injection to rodent models of metabolic disorders. Animals are treated with the compound for several weeks, and metabolic parameters such as body weight, food intake, glucose tolerance, insulin sensitivity, and lipid profiles are measured. Tissues are harvested for gene expression analysis and histopathological examination.

L-165041 has a molecular weight of 402.44 and a molecular formula of C₂₂H₂₆O₇. The compound is soluble in DMSO (30 mg/mL) and DMF (50 mg/mL). It should be stored as a crystalline solid at room temperature or as recommended by the manufacturer. The compound's purity is typically ≥95-98%. L-165041 is stable when stored properly and protected from light and moisture.

The toxicological profile of L-165041 has not been extensively characterized in the published literature. As a PPARδ agonist, it may have effects on lipid metabolism and energy balance, but comprehensive toxicology data are limited. L-165041 is not approved for human use and is strictly a research compound. It should be handled with appropriate laboratory safety precautions.

[1]. Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999 Mar 5;274(10):6718-25.

[2]. The PPARδ ligand L-165041 inhibits vegf-induced angiogenesis, but the antiangiogenic effect is not related to PPARδ. Journal of Cellular Biochemistry (2012), 113(6), 1947-1954.

[3]. PPARδ ligand L-165041 ameliorates Western diet-induced hepatic lipid accumulation and inflammation in LDLR-/- mice. European Journal of Pharmacology (2009), 622(1-3), 45-51.

[4]. PPARδ agonist L-165041 inhibits rat vascular smooth muscle cell proliferation and migration via inhibition of cell cycle. Atherosclerosis (Amsterdam, Netherlands) (2009), 202(2), 446-454.

2-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid is an aromatic ketone.

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L-165041 is a selective PPARδ agonist that has been widely used as a research tool to study PPARδ-mediated signaling and metabolism. It is not approved for clinical use and remains an experimental compound. The compound has been instrumental in elucidating the role of PPARδ in lipid metabolism, glucose homeostasis, and energy balance. L-165041 is used in preclinical research to explore potential therapeutic strategies for obesity, diabetes, and cardiovascular diseases.

C22H26O7

402.443

402.167

C, 65.66; H, 6.51; O, 27.83

79558-09-1

6603901

Typically exists as White to off-white solids at room temperature

1.2±0.1 g/cm3

600.8±55.0 °C at 760 mmHg

127-128ºC(lit.)

206.5±25.0 °C

0.0±1.8 mmHg at 25°C

1.566

4.98

2

7

12

29

501

0

O=C(COC1C=CC(OCCCOC2C(CCC)=C(O)C(C(C)=O)=CC=2)=CC=1)O

HBBVCKCCQCQCTJ-UHFFFAOYSA-N

InChI=1S/C22H26O7/c1-3-5-19-20(11-10-18(15(2)23)22(19)26)28-13-4-12-27-16-6-8-17(9-7-16)29-14-21(24)25/h6-11,26H,3-5,12-14H2,1-2H3,(H,24,25)

2-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid

L 165041; L165041; L-165041; L-165,041; 2-(4-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy)phenoxy)acetic acid; L165041; 2-(4-(3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propoxy)phenoxy)acetic acid; 2-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid; Aceticacid, 2-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]-; L-165041

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)

DMSO : ~50 mg/mL (~124.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)