The target of Muraglitazar (BMS298585) is peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ), nuclear receptors regulating glucose and lipid metabolism. For human PPARα, the half-maximal effective concentration (EC₅₀) of Muraglitazar is 0.1 μM [2]
; for human PPARγ, the EC₅₀ is 0.03 μM [2]
; it exhibits negligible activation of peroxisome proliferator-activated receptor δ (PPARδ) (EC₅₀ > 10 μM) [2]

1. PPAR reporter gene activation: In HEK293 cells transfected with PPARα/γ-responsive luciferase reporter plasmids, Muraglitazar activates human PPARα and PPARγ in a concentration-dependent manner. The maximal activation of PPARα reaches 85% of the positive control (fenofibrate), and PPARγ reaches 92% of rosiglitazone [2]
2. 3T3-L1 adipocyte differentiation: Treatment of 3T3-L1 preadipocytes with Muraglitazar (0.01–1 μM) for 14 days promotes adipocyte differentiation (Oil Red O staining), with a 2.5-fold increase in lipid accumulation at 0.1 μM compared to vehicle. It also upregulates the expression of PPARγ target genes (aP2, GLUT4) by 3–4 fold (detected by real-time PCR) [2]
3. Hepatocyte lipid metabolism: In primary human hepatocytes, Muraglitazar (0.1 μM) reduces intracellular triglyceride content by 30% and increases apoA-I secretion (a marker of HDL synthesis) by 40% [2]
4. Glucose uptake in adipocytes: In differentiated 3T3-L1 adipocytes, Muraglitazar (0.1 μM) enhances insulin-stimulated 2-deoxyglucose uptake by 50% compared to vehicle [2]

1. db/db diabetic mice: Oral administration of Muraglitazar (1, 3, 10 mg/kg/day) for 28 days leads to a dose-dependent reduction in fasting blood glucose (FBG): 20%, 35%, and 45% lower than vehicle control, respectively; glycated hemoglobin (HbA1c) is reduced by 1.2%, 2.1%, and 2.8% [2]
2. ZDF rats (type 2 diabetes model): Muraglitazar (5 mg/kg/day oral) for 12 weeks reduces FBG by 40%, triglycerides (TG) by 50%, and increases high-density lipoprotein cholesterol (HDL-C) by 30% compared to control; insulin sensitivity (hyperinsulinemic-euglycemic clamp) is improved by 60% [2]
3. 24-week clinical monotherapy: In adult patients with type 2 diabetes (n=332), oral Muraglitazar at 5 mg/day and 10 mg/day reduces HbA1c by 0.8% and 1.0%, respectively (placebo: 0.1% increase); FBG is reduced by 2.1 mmol/L (5 mg) and 2.5 mmol/L (10 mg) (placebo: 0.3 mmol/L increase) [1]
4. Lipid effects in clinical trial: Muraglitazar 5 mg/day reduces TG by 15% and increases HDL-C by 10%; 10 mg/day reduces TG by 22% and increases HDL-C by 14% (placebo: TG +2%, HDL-C 0%) [1]
5. Body weight change in clinical trial: Patients receiving Muraglitazar 5 mg/day gain a mean of 2.1 kg, and 10 mg/day gain 3.2 kg over 24 weeks, compared to 0.3 kg with placebo [1]

1. PPARα activation assay: HEK293 cells are seeded into 24-well plates (5×10⁴ cells/well) and transfected with a PPARα response element (PPRE)-luciferase reporter plasmid, human PPARα expression plasmid, and Renilla luciferase plasmid (internal control). After 24 hours of transfection, cells are treated with serial dilutions of Muraglitazar (0.001–10 μM) or vehicle for 18 hours. Cell lysates are prepared, and luciferase activity is measured using a dual-luciferase assay system. The relative luciferase activity (firefly/Renilla) is calculated, and the EC₅₀ for PPARα activation is determined from the dose-response curve [2]
2. PPARγ activation assay: The same procedure is used as the PPARα assay, with human PPARγ expression plasmid and PPRE-luciferase reporter plasmid specific to PPARγ. Muraglitazar is tested at 0.001–10 μM, and rosiglitazone is used as a positive control. The EC₅₀ for PPARγ activation is calculated from relative luciferase activity data [2]

1. 3T3-L1 adipocyte differentiation assay: 3T3-L1 preadipocytes are seeded into 6-well plates (1×10⁵ cells/well) and cultured to confluence. On day 0 (2 days post-confluence), cells are induced to differentiate with insulin, dexamethasone, IBMX, and serial dilutions of Muraglitazar (0.01–1 μM) or vehicle. The medium is refreshed every 2 days with insulin and Muraglitazar. On day 14, cells are fixed with formalin, stained with Oil Red O, and the dye is eluted with isopropanol for absorbance measurement at 510 nm. Total RNA is extracted, and aP2/GLUT4 gene expression is analyzed by real-time PCR [2]
2. Primary human hepatocyte lipid metabolism assay: Primary human hepatocytes are seeded into collagen-coated plates (2×10⁵ cells/well) and cultured for 48 hours. Cells are treated with Muraglitazar (0.01–1 μM) or vehicle for 24 hours. Intracellular triglyceride content is measured by a colorimetric kit, and apoA-I secretion in the medium is quantified by ELISA [2]
3. Glucose uptake assay in 3T3-L1 adipocytes: Differentiated 3T3-L1 adipocytes are serum-starved for 4 hours, then treated with Muraglitazar (0.1 μM) or vehicle for 18 hours. Insulin (100 nM) is added for 30 minutes, followed by 2-deoxy-[¹⁴C]-glucose. Cells are washed, lysed, and intracellular radioactivity is measured by a scintillation counter to determine glucose uptake efficiency [2]

1. db/db diabetic mouse study: Male db/db mice (8–10 weeks old) are randomized into four groups (n=10 per group): vehicle (0.5% CMC) and Muraglitazar 1, 3, 10 mg/kg/day. The drug is formulated as a 0.5% CMC suspension and administered orally by gavage once daily for 28 days. FBG is measured weekly via tail vein glucometry, and HbA1c is determined by HPLC at the end of the study. Body weight and food intake are monitored daily [2]
2. ZDF rat study: Male ZDF rats (6 weeks old) are assigned to vehicle or Muraglitazar 5 mg/kg/day groups (n=8 per group). The drug is given orally by gavage once daily for 12 weeks. Blood samples are collected monthly to measure FBG, TG, total cholesterol, HDL-C, and LDL-C via clinical chemistry analyzers. Insulin sensitivity is assessed at week 10 using a hyperinsulinemic-euglycemic clamp [2]
3. 24-week clinical trial protocol: Adult patients with type 2 diabetes (HbA1c 7.0–10.0%) are randomized to placebo, Muraglitazar 5 mg/day, or 10 mg/day (n=112, 110, 110 per group) in a double-blind, parallel design. The drug is administered orally once daily with food for 24 weeks. HbA1c, FBG, lipid profiles, body weight, and adverse events are assessed at baseline and every 4 weeks [1]

Metabolism / Metabolites
Known human metabolites of Muraglitazar include N-((4-hydroxyphenyl)methyl)-N-((4-methoxyphenoxy)carbonyl)glycine, 9-hydroxy Muraglitazar, 17-hydroxy Muraglitazar, O-demethyl Muraglitazar, and 12-hydroxy Muraglitazar.

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1. Oral absorption: Muraglitazar has high oral bioavailability (≈90%) after a single oral dose of 5 mg in humans; peak plasma concentration (Cmax) is reached 2-4 hours after administration [2]
2. Plasma half-life: Muraglitazar has a terminal plasma half-life (t₁/₂) of approximately 24 hours in humans, supporting once-daily administration [2]
3. Distribution: Muraglitazar has a volume of distribution (Vd) of 120 L in humans and crosses the blood-brain barrier very rarely (brain/plasma ratio <0.1) [2]
4. Metabolism: Muraglitazar is mainly metabolized in the liver via CYP3A4 to form inactive hydroxylated metabolites (M1, M2); less than 5% of the original drug is excreted unchanged [2]
5. Excretion: In the human body, approximately 70% of the dose is excreted in feces (as metabolites) within 7 days, and approximately 20% is excreted in urine [2]. 6. Plasma protein binding rate: Muraglitazar binds to human plasma proteins (mainly albumin) at a rate of 99.5%, and its binding rate is concentration-independent within the therapeutic concentration range (0.01–1 μM) [2].

1. Clinical adverse events: In the 24-week trial, the most common adverse events with Muraglitazar were peripheral edema (15% in the 5 mg group, 22% in the 10 mg group, and 5% in the placebo group), weight gain (2.1 kg in the 5 mg group, 3.2 kg in the 10 mg group, and 0.3 kg in the placebo group) and headache (10% in the placebo group and 8% in the placebo group)[1] 2. Cardiovascular safety: Post-hoc analysis showed that Muraglitazar increased the risk of major adverse cardiovascular events (MACE) (myocardial infarction, stroke) compared with placebo (HR 1.8, 95% CI 1.1–2.9)[2] 3. Animal toxicity: In a 6-month rat study, Muraglitazar 30 mg/kg/day (10 times the treatment dose) caused cardiac hypertrophy (increased by 15%). Decreased heart weight/body weight ratio) and mild hepatic steatosis, which are reversible upon discontinuation of the drug [2]
4. Drug interactions: Co-administration with ketoconazole (a CYP3A4 inhibitor) increases plasma Muraglitazar concentration by 1.5 times; co-administration with rifampin (a CYP3A4 inducer) decreases concentration by 40% [2]
5. Hepatotoxicity/nephrotoxicity: In clinical trials, no significant increase in serum creatinine or liver enzymes (ALT/AST) was observed with therapeutic doses of Muraglitazar [1]

[1]. Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin Ther. 2005;27(8):1181-1195.

[2]. Muraglitazar: an agent for the treatment of type 2 diabetes and associated dyslipidemia. Drugs Today (Barc). 2005;41(9):579-587.

Mulagrieza belongs to the 1,3-oxazole class of compounds. Mulagrieza (Bristol-Myers Squibb/Merck) is a novel drug being investigated for the treatment of type 2 diabetes. It is a novel drug that targets the α and γ subtypes of peroxisome proliferator-activated receptor (PPAR). In addition to improving blood glucose and glycated hemoglobin (HbA1c) levels, mulagrieza treatment significantly reduces triglyceride (TG) levels, increases high-density lipoprotein cholesterol (HDL-C) levels, and moderately reduces low-density lipoprotein cholesterol (LDL-C) levels. Mulagrieza is a dual peroxisome proliferator-activated receptor (PPAR) agonist with hypoglycemic activity. Mulagrieza increases HDL-C levels and decreases total cholesterol, apolipoprotein B, triglycerides, and HbA1c levels. This drug is associated with an increased risk of adverse cardiovascular events and heart failure.
Drug Indications
Studied for the treatment of type 2 diabetes.

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Mechanism of Action
Mograjeza is a dual peroxisome proliferator-activated receptor (PPAR) agonist. It interacts with both PPARα and γ receptors. Mograjeza acts through PPARγ receptors and has a very strong insulin-sensitizing effect on the liver and muscles, thereby reducing blood glucose levels. Mograjeza can effectively reduce triglyceride levels, increase high-density lipoprotein cholesterol (HDL-C) levels, and convert small and dense low-density lipoprotein (LDL-C) particles into larger and more buoyant particles by acting on PPARα receptors, thereby improving the lipid profile from the perspective of preventing atherosclerosis.

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1. Mograjeza (BMS298585) is a dual PPARα/γ agonist developed by Bristol-Myers Squibb to improve insulin sensitivity (PPARγ) and dyslipidemia (PPARα) in patients with type 2 diabetes and to treat metabolic syndrome complications[2]. 2. Mechanism of action: Molagrieza binds to and activates PPARα/γ, thereby regulating gene expression in glucose/lipid metabolism. PPARγ enhances insulin sensitivity in fat, muscle, and liver; PPARα upregulates fatty acid oxidation and high-density lipoprotein (HDL) synthesis in the liver [1]
3. Clinical efficacy: In a 24-week trial, 35% (5 mg) and 42% (10 mg) of patients achieved HbA1c levels below 7.0%, compared to only 10% in the placebo group (p<0.001) [1]
4. Regulatory status: Muraglitazar has never been approved by the FDA/EMA due to cardiovascular safety concerns, and its development was terminated in 2006 [2]
5. Comparison with other PPAR agonists: Muraglitazar has balanced PPARα/γ activity and has shown superior hypoglycemic/lipid-lowering combined effects in preclinical models compared to PPARγ-selective drugs (rosiglitazone) or PPARα-selective drugs (fenofibrate) [2]

C29H28N2O7

516.54182

516.19

C, 67.43; H, 5.46; N, 5.42; O, 21.68

331741-94-7

331741-94-7

206044

Solid powder

1.274g/cm3

736.4ºC at 760 mmHg

399.2ºC

1.601

4.819

1

8

12

38

730

0

CC1=C(CCOC2=CC=C(C=C2)CN(CC(=O)O)C(=O)OC3=CC=C(C=C3)OC)N=C(C4=CC=CC=C4)O1

IRLWJILLXJGJTD-UHFFFAOYSA-N

InChI=1S/C29H28N2O7/c1-20-26(30-28(37-20)22-6-4-3-5-7-22)16-17-36-24-10-8-21(9-11-24)18-31(19-27(32)33)29(34)38-25-14-12-23(35-2)13-15-25/h3-15H,16-19H2,1-2H3,(H,32,33)

2-[(4-methoxyphenoxy)carbonyl-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]amino]acetic acid

Muraglitazar; Pargluva; BMS298585; BMS 298585; BMS-298585

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)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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