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| Targets |
Naveglitazar targets peroxisome proliferator-activated receptors (PPARs), specifically PPARγ and PPARα. PPARγ is a nuclear receptor that regulates glucose metabolism and insulin sensitivity, and its activation improves glycemic control. PPARα is a nuclear receptor that regulates lipid metabolism, and its activation reduces triglyceride levels and improves lipid profiles. By acting as a dual PPARγ/PPARα agonist, Naveglitazar has the potential to improve both glucose and lipid metabolism in patients with type 2 diabetes. The compound's dual mechanism may provide broader metabolic benefits compared to selective PPAR agonists.
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| ln Vitro |
The non-thiazolidinedione (TZD) naveglitazar has a unique profile that could lead to a better therapeutic agent for the treatment of type 2 diabetes and related dyslipidemia. It works as a strong and effective insulin sensitizer in rodents. By ultracentrifuging mouse, rat, and monkey plasma, the degree of [3H]Naveglitazar's in vitro binding to plasma proteins is assessed. After in vitro incubation at 37 °C for 60 min, the mean percentages±SEM of protein binding of radioactivity in plasma over the concentration range of 0.1 to 1000 ng/ml are 99.5%±0.1% for mice, 99.6%±0.1% for rats, and 99.6%±0.3% for monkeys. According to these findings, naveglitazar has a strong binding to plasma proteins across all species studied, and this binding is concentration-independent[1].
In vitro, Naveglitazar activates PPARγ and PPARα in cell-based reporter assays. In PPARγ transactivation assays, the compound shows potent agonist activity, with EC₅₀ values in the nanomolar range. In PPARα transactivation assays, Naveglitazar also shows agonist activity, although the potency may be lower than for PPARγ. The compound's activity is typically assessed by measuring the activation of PPAR-responsive luciferase reporter genes in transfected cells. Naveglitazar also induces the expression of PPAR target genes involved in glucose and lipid metabolism. The compound's in vitro activity supports its development as an antidiabetic agent. |
| ln Vivo |
[14C]Naveglitazar is rapidly absorbed and moderately metabolized before elimination. Following oral dosing, 47, 31, and 62% of the radioactivity, as measured by AUC values, circulates as metabolites in mice, rats, and monkeys, respectively. The half-lives of Naveglitazar and radioactivity are similar in each species; however, monkeys have significantly longer half-lives than mice and rats. Naveglitazar and radioactivity are gradually eliminated from system circulation in all tested species[1].
In vivo, Naveglitazar has been studied in animal models of type 2 diabetes and in clinical trials. The compound improves glycemic control, insulin sensitivity, and lipid profiles in diabetic animal models. In clinical trials, Naveglitazar was evaluated for the treatment of type 2 diabetes mellitus. However, the compound's clinical development may have been discontinued due to safety concerns or lack of efficacy, as is common with many PPAR agonists. Specific efficacy data are available from clinical trial publications. |
| Enzyme Assay |
In vitro receptor binding assays for Naveglitazar typically involve measuring the activation of PPARγ and PPARα in transactivation assays. A typical protocol: HEK293 or COS-7 cells are transfected with plasmids encoding human PPARγ or PPARα and a luciferase reporter gene under the control of a PPAR-responsive element (PPRE). Cells are treated with Naveglitazar at concentrations ranging from 0.1 nM to 10 μM for 16-24 hours. Luciferase activity is measured using a luminometer. EC₅₀ values are calculated from dose-response curves. Positive controls include rosiglitazone (for PPARγ) and fenofibrate (for PPARα). Each concentration is tested in triplicate, and experiments are repeated at least three times.
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| Cell Assay |
In vitro cell-based assays for Naveglitazar are performed using adipocyte or hepatocyte cell lines. A typical protocol: 3T3-L1 preadipocytes are differentiated into adipocytes and treated with Naveglitazar at concentrations ranging from 0.01 to 10 μM for 24-72 hours. Adipocyte differentiation is assessed by Oil Red O staining and by measuring the expression of adipocyte markers (e.g., PPARγ, aP2, adiponectin) by qRT-PCR. For hepatocyte assays, HepG2 cells are treated with Naveglitazar, and the expression of PPARα target genes (e.g., CPT1a, ACOX1) is measured by qRT-PCR. Glucose uptake is measured using 2-deoxyglucose uptake assays. Each condition is tested in triplicate, and experiments are repeated at least three times.
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| Animal Protocol |
In vivo animal studies for Naveglitazar were conducted in rodent models of type 2 diabetes. A typical protocol: male db/db mice or Zucker diabetic fatty (ZDF) rats are administered Naveglitazar via oral gavage at doses of 1-30 mg/kg, daily for 2-4 weeks. Blood glucose and insulin levels are measured at regular intervals. Oral glucose tolerance tests (OGTT) are performed to assess glucose tolerance. Plasma lipid profiles (triglycerides, total cholesterol, HDL, LDL) are measured. Insulin sensitivity is assessed by homeostatic model assessment (HOMA) or by hyperinsulinemic-euglycemic clamp studies. At study termination, tissues are harvested for histopathological examination and biomarker analysis.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Naveglitazar have been characterized in preclinical studies. The compound is orally bioavailable. Following oral administration, Naveglitazar is absorbed and reaches therapeutic concentrations in the systemic circulation. Its half-life, volume of distribution, clearance, and protein binding have been evaluated in preclinical models. The compound is soluble in DMSO, not in water. The compound is metabolized in the liver, and its metabolites are eliminated via the renal and biliary routes. Specific pharmacokinetic parameters have been reported in preclinical studies.
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| Toxicity/Toxicokinetics |
Toxicological data for Naveglitazar have been evaluated in preclinical safety studies. As a PPAR agonist, the compound may have class-related adverse effects, including fluid retention, weight gain, and hepatotoxicity. The compound has not been associated with significant organ toxicity in preclinical studies at therapeutic doses. Standard laboratory safety precautions should be followed when handling Naveglitazar: use of personal protective equipment (gloves, safety goggles, lab coat) and handling in a well-ventilated fume hood. The compound should be stored as recommended by the manufacturer. Researchers should consult the safety data sheet (SDS) before handling.
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| References | |
| Additional Infomation |
Naveglitazar is an aromatic ether. It has been used in clinical trials for the treatment of non-insulin-dependent diabetes mellitus. Naveglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist with hypoglycemic activity. Naveglitazar has a higher affinity for PPARγ than for PPARα. Naveglitazar and its metabolites are primarily excreted via bile.
Additional information for Naveglitazar: The compound has a CAS number of 476436-68-7. Its molecular formula is C₂₅H₂₆O₆ and molecular weight is 422.47 g/mol. Synonyms include LY 519818. It is a dual PPARγ/PPARα agonist. It was studied for the treatment of type 2 diabetes mellitus. It was evaluated in clinical trials (NCT00065312). It is soluble in DMSO, not in water. It is for research use only and is not approved for clinical applications. No FDA approvals exist. |
| Molecular Formula |
C25H26O6
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| Molecular Weight |
422.477
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| Exact Mass |
422.173
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| CAS # |
476436-68-7
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| Related CAS # |
Naveglitazar racemate;916085-47-7
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| PubChem CID |
9888484
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.968
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
31
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| Complexity |
490
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CO[C@@H](CC1=CC=C(C=C1)OCCCOC2=CC=C(C=C2)OC3=CC=CC=C3)C(=O)O
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| InChi Key |
OKJHGOPITGTTIM-DEOSSOPVSA-N
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| InChi Code |
InChI=1S/C25H26O6/c1-28-24(25(26)27)18-19-8-10-20(11-9-19)29-16-5-17-30-21-12-14-23(15-13-21)31-22-6-3-2-4-7-22/h2-4,6-15,24H,5,16-18H2,1H3,(H,26,27)/t24-/m0/s1
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| Chemical Name |
(2S)-2-methoxy-3-[4-[3-(4-phenoxyphenoxy)propoxy]phenyl]propanoic acid
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| Synonyms |
LY 519818 LY-519818 LY519818
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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 | 2.3670 mL | 11.8349 mL | 23.6698 mL | |
| 5 mM | 0.4734 mL | 2.3670 mL | 4.7340 mL | |
| 10 mM | 0.2367 mL | 1.1835 mL | 2.3670 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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