| Size | Price | Stock | Qty |
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| 100mg |
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| 500mg |
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| 1g | |||
| Other Sizes |
| Targets |
PPARα
GW590735 targets peroxisome proliferator-activated receptor alpha (PPARα) with high potency and selectivity. It is a ligand-activated transcription factor that regulates genes involved in lipid metabolism, including apolipoprotein A-I (ApoA-I) and apolipoprotein C-III (ApoC-III). GW590735 exhibits an EC50 of 4 nM for the expression of a GAL4-responsive reporter gene and shows at least 500-fold selectivity over PPARγ and PPARδ. This high selectivity makes it a valuable tool for dissecting PPARα-specific biological pathways without confounding effects from other PPAR isoforms. |
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| ln Vitro |
The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance[1].
In vitro, GW590735 acts as a potent PPARα agonist with an EC50 of 4 nM in GAL4-responsive reporter gene assays. It demonstrates at least 500-fold selectivity for PPARα over PPARγ and PPARδ, confirming its specificity for the alpha isoform. The compound activates PPARα-mediated transcriptional activity, leading to the upregulation of genes involved in fatty acid oxidation and lipoprotein metabolism. These in vitro properties establish GW590735 as a highly selective tool for studying PPARα-dependent signaling pathways in cell-based systems. |
| ln Vivo |
GW 590735 (0.5–5 mg/kg; PO twice daily for 5 days) raises HDL cholesterol and lowers LDLc and TG in an Apo-AI transgenic mouse model (human transgenic male C57BL/6 mice). APOA-II)(1). Cl, Vd, T1/2, and F% of GW 590735 (IV; 2.7 mg/kg; rat) were displayed after 2.4 hours, 1 L/kg, 5 mL/min/kg, and 47%, respectively [1]. The results of treatment with GW 590735 (IV; 2 mg/kg; dog) showed that Cl, Vd, T1/2, and F% were, respectively, 13 mL/min/kg, 2.8 L/kg, 2.6 hours, and 85% [1].
In vivo, GW590735 significantly increases HDL cholesterol while decreasing LDL and VLDL cholesterol levels in animal models. It also dramatically reduces triglycerides, with maximum increases in HDL cholesterol reported at approximately 37%. These lipid-modulating effects are consistent with PPARα activation and the subsequent regulation of apolipoprotein expression. The compound has been evaluated in preclinical models of dyslipidemia and shows promise for studying PPARα-mediated metabolic improvements. |
| Enzyme Assay |
The protein was then diluted to 1 mg/mL with buffer C such that the final buffer composition was 220 mM ammonium acetate, 20 mM HEPES pH 7.5, 1 mM EDTA, and 1 mM DTT. The peptide SRC116 was added in a molar ratio of 1.5 as a 2 mg/100 μL DMSO stock. The ligand was then added in a 5:1 molar ratio as a 2 mg/100 μL DMSO stock and spun at 4 K for 20 min to clarify the solution before concentrating in Centriprep 10 filtration units. The solution containing the PPARα LBD-SRC1 complexes was concentrated to approximately 10 mg/mL with 80% yield[1].
The in vitro enzyme/receptor binding assay for GW590735 typically involves a GAL4-responsive reporter gene system. In this assay, cells are transfected with a construct expressing the GAL4 DNA-binding domain fused to the PPARα ligand-binding domain, along with a reporter plasmid containing GAL4-responsive elements upstream of a luciferase gene. Test compound is added at various concentrations, and after an appropriate incubation period, luciferase activity is measured to determine the EC50 for PPARα activation. Selectivity over PPARγ and PPARδ is assessed using similar reporter systems with the respective PPAR isoforms. |
| Cell Assay |
The PPARα ligand binding domain (amino acids 192−468) with an N-terminal 6xHis tag was expressed using the T7 promoter of plasmid vector pRSETA. BL21(DE3) E. coli cells transformed with this expression vector were grown at 24 °C in shaker flasks for 66 h. The cells were harvested, resuspended, and lysed. The lysed cells were centrifuged, and the supernatant was loaded on a Ni-agarose column. The column was washed with 150 mL of buffer A (10% glycerol, 20 mM HEPES pH 7.5, 25 mM imidazole), and the protein was eluted with a 450 mL gradient of buffer B (10% glycerol, 20 mM HEPES pH 7.5, 500 mM imidazole). The protein, which eluted at 20% buffer B, was diluted with one volume of buffer C (20 mM HEPES, pH 7.5, 1 mM EDTA) and loaded on a 100 mL S-Sepharose column. The column was washed with 100 mL buffer C, and the PPARα LBD protein was eluted with a 200 mL gradient of buffer D (20 mM HEPES, pH 7.5, 10 mM DTT, 1 M ammonium acetate). The PPARα LBD eluted from the column at 43% buffer D. The protein yield was 9 mg/L of cells grown and was >95% pure, as determined by SDS-PAGE analysis[1].
The in vitro cell-based assay for GW590735 involves culturing appropriate cell lines (e.g., HEK293 or HepG2 cells) that have been transiently transfected with PPARα reporter constructs. Cells are seeded in multi-well plates and allowed to adhere overnight. GW590735 is then added at a range of concentrations (typically from nanomolar to micromolar) and incubated for 16-24 hours. Following incubation, cells are lysed and luciferase activity is measured using a luminometer. EC50 values are calculated from dose-response curves. Cytotoxicity may be assessed simultaneously using a cell viability assay such as MTT or CellTiter-Glo. |
| Animal Protocol |
Apo-A-I Transgenic Mouse Model. [1]Male C57BL/6 mice transgenic for human ApoA-I were randomized into treatment groups of n = 5 animals. Twice a day oral administration of vehicle (0.5% HPMC/1% Tween80, pH = 7.0) or indicated doses of compound as a suspension began when animals were nine weeks old and lasted for 5 days. Animals were fasted overnight before blood samples were taken by intracardiac puncture. Whole liver was collected and weighed. Blood samples were left for 30 min at 37 °C to coagulate and centrifuged 10 min at 10 000 rpm. Total serum fraction was then collected and frozen at −20 °C until use. Total cholesterol and total TG were dosed using kits 61219 and 61236, respectively, following manufacturer instructions. After 10 min of incubation at 37 °C, the colorimetric reaction was read at 492 nm with an iEMS reader. Cholesterol HDL, LDL, and VLDL fractions were separated by HPLC. Samples were diluted 1/5 in phosphate buffer (Ca++ and Mg- free) and filtered on 0.45 μm to remove excess proteins before HPLC. All changes reported with an asterisk are statistically significant (p < 0.05) as determined by one-way ANOVA analysis.
In vivo animal studies for GW590735 are typically conducted in rodent models of dyslipidemia, such as high-fat diet-fed mice or genetically hyperlipidemic strains. Animals are administered GW590735 orally or via intraperitoneal injection at various doses (e.g., 1-30 mg/kg) for a period of 1-4 weeks. Blood samples are collected at baseline and at regular intervals during treatment for analysis of lipid profiles, including total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides. Liver and adipose tissue may also be collected for gene expression analysis and histopathological examination. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of GW590735 include oral bioavailability and favorable tissue distribution, consistent with its efficacy in vivo. As a small-molecule PPARα agonist, it is expected to be metabolized primarily in the liver via cytochrome P450 enzymes. The compound likely exhibits moderate to high protein binding and a half-life suitable for once- or twice-daily dosing in preclinical studies. Detailed PK parameters such as Cmax, Tmax, AUC, and half-life are typically determined in rodent or non-rodent species following single or multiple dose administration.
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| Toxicity/Toxicokinetics |
The toxicity profile of GW590735 has been characterized in preclinical studies. As a research compound, it is not approved for human use, and safety data are primarily derived from animal models. Common findings with PPARα agonists may include hepatomegaly (liver enlargement) and peroxisome proliferation in rodents, which are considered species-specific effects that may not translate to humans. No significant genotoxicity or carcinogenicity has been reported in available literature. Standard toxicology studies include acute, sub-chronic, and chronic dosing in rodents and dogs, with endpoints including clinical signs, body weight, food consumption, clinical pathology, and histopathology.
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| References | |
| Additional Infomation |
GW590735 is a research compound and has not been approved for clinical use or marketed as a therapeutic agent. Its primary application is in preclinical metabolic research, particularly for studying PPARα-mediated regulation of lipid metabolism and dyslipidemia. The compound was first described in the literature in 2007 as part of a series of substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARα agonists. It continues to be used as a pharmacological tool to investigate the role of PPARα in metabolic diseases, including dyslipidemia, atherosclerosis, and non-alcoholic fatty liver disease.
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| Molecular Formula |
C23H21F3N2O4S
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|---|---|
| Molecular Weight |
478.486
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| Exact Mass |
478.117
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| Elemental Analysis |
C, 57.73; H, 4.42; F, 11.91; N, 5.85; O, 13.37; S, 6.70
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| CAS # |
622402-22-6
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| Related CAS # |
343322-50-9 (sodium); 622402-22-6 (free acid); 343321-96-0
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| PubChem CID |
9956726
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| Appearance |
Solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.572
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| LogP |
5.22
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
690
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| Defined Atom Stereocenter Count |
0
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| SMILES |
OC(C(OC1C=CC(CNC(C2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)=O)=CC=1)(C)C)=O
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| InChi Key |
ILUPZUOBHCUBKB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H21F3N2O4S/c1-13-18(33-20(28-13)15-6-8-16(9-7-15)23(24,25)26)19(29)27-12-14-4-10-17(11-5-14)32-22(2,3)21(30)31/h4-11H,12H2,1-3H3,(H,27,29)(H,30,31)
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| Chemical Name |
2-methyl-2-(4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxamido)methyl)phenoxy)propanoic acid
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| Synonyms |
GW590735; GW-590735; GW 590735.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0899 mL | 10.4495 mL | 20.8991 mL | |
| 5 mM | 0.4180 mL | 2.0899 mL | 4.1798 mL | |
| 10 mM | 0.2090 mL | 1.0450 mL | 2.0899 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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