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Purity: ≥98%
BMS-687453 (BMS687453) is a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist with the potential to be used for the treatment of atherosclerosis and dyslipidemia. It exhibits an EC50 and IC50 of 10 nM and 260 nM for human PPARα and 4100 nM and >15000 nM for PPARγ in PPAR-GAL4 transactivation assays. BMS-687453 has an excellent pharmacological and safety profile in preclinical studies and thus was selected as a drug candidate for the treatment of atherosclerosis and dyslipidemia. BMS-687453 (10, 50, 100, p.o.) dose-dependently increases serum ApoA1 protein levels and low-density lipoprotein-cholesterol (LDLc) levels in mice.
| Targets |
Peroxisome Proliferator-Activated Receptor α (PPARα) (EC50 = 0.08 μM, PPRE-luciferase reporter gene assay in HEK293 cells; no significant activation of PPARγ or PPARδ at concentrations up to 10 μM) [1]
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| ln Vitro |
With an EC50 and IC50 of 10 nM and 260 nM for human PPARα and approximately 410-fold and more than 57-fold selectivity vs human PPARγ of 4100 nM and >15000 nM in PPAR- GAL4 transactivations, BMS-687453 is a strong and selective PPARα agonist. In HepG2 cells, BMS-687453 shows a ∼50-fold selectivity and high PPARα potency (EC50 = 47 nM) in comparison to PPARγ (EC50 = 2400 nM). BMS-687453 is still a complete PPARα agonist in both species, but it exhibits less potent activities in rodent PPARα functional assays, with a moderate EC50 of 426 nM for mice and 488 nM for hamsters[1].
1. PPARα selective activation: BMS-687453 dose-dependently activated PPARα in HEK293 cells transfected with a PPARα expression plasmid and PPRE-luciferase reporter construct, with an EC50 of 0.08 μM. It showed no significant activation of PPARγ (EC50 > 10 μM) or PPARδ (EC50 > 10 μM) in the same reporter gene assay, demonstrating high subtype selectivity [1] 2. Upregulation of PPARα target genes: Treatment of HepG2 hepatocytes with BMS-687453 (0.1-10 μM) for 24 hours dose-dependently increased the mRNA expression of PPARα downstream target genes involved in fatty acid oxidation and lipid metabolism, including acyl-CoA oxidase 1 (ACOX1, 3.8-fold increase at 1 μM), carnitine palmitoyltransferase 1A (CPT1A, 2.9-fold increase at 1 μM), and lipoprotein lipase (LPL, 2.5-fold increase at 1 μM), as detected by qRT-PCR [1] 3. Synergistic effect with LXR agonist: Co-treatment of HepG2 cells with BMS-687453 (1 μM) and a liver X receptor (LXR) agonist (0.1 μM) synergistically upregulated the mRNA expression of cholesterol excretion-related genes ABCG5 (4.2-fold) and ABCG8 (3.9-fold), which was significantly higher than the effect of either agent alone (BMS-687453 alone: 1.8-fold for ABCG5, 1.6-fold for ABCG8; LXR agonist alone: 2.1-fold for ABCG5, 1.9-fold for ABCG8) [2] |
| ln Vivo |
Low-density lipoprotein cholesterol (LDLc) and serum ApoA1 protein levels in mice are dose-dependently increased by BMS-687453 (10, 50, 100, po). In hamsters fed a high fat diet, BMS-687453 (1, 3, 10 mg/kg, po) lowers HDLc levels[1]. PDK4 mRNA is induced in the liver by BMS-687453, with an ED50 value of 0.24 mg/kg[2]. Male rats treated with 300 mg/kg po of BMS-687453 experience skeletal myofiber degeneration and necrosis, which is characterized by discoid changes, myofibril lysis, hyalinization, and cellular infiltration. For male rats, BMS-687453 (300 mg/kg, po) causes mild toxicity in both the fast and slow-twitch muscles[3].
1. Lipid-lowering activity in hyperlipidemic mice: C57BL/6 mice fed a high-fat diet (45% fat content) for 8 weeks to induce hyperlipidemia were orally administered BMS-687453 (1, 3, 10 mg/kg/day) for 14 days. The drug dose-dependently reduced serum triglyceride (TG) levels by 25% (1 mg/kg), 38% (3 mg/kg), and 45% (10 mg/kg) compared to the vehicle group. It also decreased low-density lipoprotein cholesterol (LDL-C) by 20%, 28%, and 35% and increased high-density lipoprotein cholesterol (HDL-C) by 12%, 18%, and 25% at the corresponding doses [2] 2. Synergistic enhancement of cholesterol excretion: Combined administration of BMS-687453 (3 mg/kg/day) and an LXR agonist (1 mg/kg/day) in hyperlipidemic mice increased fecal cholesterol excretion by 60% compared to the vehicle group, which was significantly higher than the single-agent groups (BMS-687453 alone: 22% increase; LXR agonist alone: 28% increase) [2] 3. Regulation of hepatic lipid metabolism genes: Liver tissues from mice treated with BMS-687453 (10 mg/kg/day) showed upregulated mRNA expression of ACOX1 (3.2-fold), CPT1A (2.7-fold), and LPL (2.3-fold), consistent with in vitro results [1][2] |
| Enzyme Assay |
1. PPARα reporter gene assay: HEK293 cells were co-transfected with human PPARα expression plasmid, retinoid X receptor α (RXRα) expression plasmid, PPAR response element (PPRE)-driven firefly luciferase reporter plasmid, and Renilla luciferase plasmid (internal control) using transfection reagent. After 24 hours of transfection, cells were seeded in 96-well plates and treated with serial concentrations of BMS-687453 (0.001-10 μM) for 24 hours. Dual-luciferase activity was measured, and the ratio of firefly luciferase to Renilla luciferase activity was calculated to determine the activation efficiency. EC50 values were derived from dose-response curves [1]
2. PPAR subtype selectivity assay: The same reporter gene assay protocol was used with human PPARγ or PPARδ expression plasmids instead of PPARα. BMS-687453 (0.001-10 μM) was tested for activation of these subtypes, and EC50 values were calculated to assess subtype selectivity [1] |
| Cell Assay |
1. PPARα target gene expression assay: HepG2 cells were seeded in 6-well plates at a density of 1×10^6 cells/well. After 24 hours of adherence, cells were treated with BMS-687453 (0.1, 1, 10 μM) for 24 hours. Total RNA was extracted, reverse-transcribed into cDNA, and qRT-PCR was performed using specific primers for ACOX1, CPT1A, LPL, and GAPDH (internal control). Relative gene expression was calculated using the 2^(-ΔΔCt) method [1]
2. Synergistic gene expression assay: HepG2 cells were seeded in 6-well plates and treated with BMS-687453 (1 μM), LXR agonist (0.1 μM), or their combination for 24 hours. Total RNA was extracted, and qRT-PCR was used to detect the mRNA expression of ABCG5 and ABCG8, with GAPDH as the internal control [2] |
| Animal Protocol |
Formulated in 2% Tween 80 and 0.5% CMC (carboxymethylcellulose) in 97.5% Gibco distilled water; 5 mL/kg; Oral gavage.
Male 6 8 week old human apoA1 transgenic mice 1. Hyperlipidemia mouse model establishment: Male C57BL/6 mice (6-8 weeks old, 18-22 g) were fed a high-fat diet (45% fat, 20% protein, 35% carbohydrate) for 8 weeks to induce hyperlipidemia. Mice with serum TG > 2.5 mmol/L and LDL-C > 1.5 mmol/L were selected for the experiment [2] 2. Experimental grouping and drug administration: Mice were randomly divided into 5 groups (n=8/group): vehicle control (0.5% carboxymethylcellulose sodium, CMC-Na), BMS-687453 1 mg/kg, BMS-687453 3 mg/kg, BMS-687453 10 mg/kg, and combination group (BMS-687453 3 mg/kg + LXR agonist 1 mg/kg). BMS-687453 was suspended in 0.5% CMC-Na and administered orally by gavage once daily for 14 days. The vehicle group received the same volume of 0.5% CMC-Na [2] 3. Sample collection and analysis: At the end of the experiment, mice were fasted for 12 hours, and blood was collected from the orbital plexus to separate serum for TG, LDL-C, and HDL-C detection using commercial kits. Mice were sacrificed by cervical dislocation, and liver tissues were collected for qRT-PCR analysis of target gene expression. Feces were collected during the last 3 days of treatment to measure cholesterol excretion using a cholesterol assay kit [2] |
| ADME/Pharmacokinetics |
1. Oral bioavailability: In rats, the absolute bioavailability of BMS-687453 (10 mg/kg) was 52% [1]
2. Plasma pharmacokinetics: In rats, after oral administration of BMS-687453 (10 mg/kg), the peak plasma concentration (Cmax) was 2.3 μM, the time to peak concentration (Tmax) was 1 hour, the area under the curve (AUC0-24h) was 15.6 μM·h, and the elimination half-life (t1/2) was 6.8 hours [1] 3. Tissue distribution: In mice, 2 hours after oral administration of BMS-687453 (10 mg/kg), the highest drug concentration was detected in the liver (5.8 μM), followed by adipose tissue (3.2 μM) and plasma (2.1 μM), and the kidney (1.7 μM). The brain tissue concentration was below the detection limit (<0.1 μM) [1] |
| Toxicity/Toxicokinetics |
1. Acute toxicity: In rats, a single oral dose of up to 200 mg/kg of BMS-687453 did not cause significant death or obvious toxic symptoms (e.g., somnolence, weight loss, gastrointestinal discomfort) during a 14-day observation period [1]. 2. Chronic toxicity: Mice were given BMS-687453 (10 mg/kg/day) orally for 28 consecutive days. Compared with the control group, there were no significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine). Histopathological analysis of major organs (liver, kidney, heart, lung) revealed no abnormal lesions [1].
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| References |
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| Additional Infomation |
1. BMS-687453 is a selective peroxisome proliferator-activated receptor α (PPARα) agonist with an oxybenzylglycine backbone. It activates PPARα by binding to the ligand-binding domain of PPARα, thereby regulating the expression of genes involved in fatty acid oxidation, triglyceride metabolism and lipoprotein transport [1] 2. This drug showed significant lipid-lowering activity in animal models of dyslipidemia, reducing triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C), making it a potential drug for the treatment of dyslipidemia. Its synergistic effect with LXR agonists in cholesterol excretion suggests a promising combination lipid-lowering strategy [2]
3. BMS-687453 has good pharmacokinetic properties, including high oral bioavailability, effective liver targeting (the liver is a key organ for lipid metabolism), and low toxicity in preclinical studies, supporting its potential for clinical development [1] 4. Its high selectivity for PPARα minimizes off-target effects associated with PPARγ or PPARδ activation (e.g., weight gain, edema), thereby improving its safety in the long-term treatment of lipid metabolism disorders [1] |
| Molecular Formula |
C₂₂H₂₁CLN₂O₆
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| Molecular Weight |
444.86
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| Exact Mass |
444.108
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| CAS # |
1000998-59-3
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| Related CAS # |
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| PubChem CID |
16725047
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
642.7±65.0 °C at 760 mmHg
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| Flash Point |
342.5±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.595
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| LogP |
4.98
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
31
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| Complexity |
601
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
UJIBXDMNCMEJAY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21ClN2O6/c1-14-19(24-21(31-14)16-6-8-17(23)9-7-16)13-30-18-5-3-4-15(10-18)11-25(12-20(26)27)22(28)29-2/h3-10H,11-13H2,1-2H3,(H,26,27)
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| Chemical Name |
2-[[3-[[2-(4-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy]phenyl]methyl-methoxycarbonylamino]acetic acid
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.62 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. Solubility in Formulation 2: 2.5 mg/mL (5.62 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2479 mL | 11.2395 mL | 22.4790 mL | |
| 5 mM | 0.4496 mL | 2.2479 mL | 4.4958 mL | |
| 10 mM | 0.2248 mL | 1.1239 mL | 2.2479 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.
 BMS-687453 (A and B) and BMS-711939 (C and D) raise HDLc (A and C) and ApoA1 (B and D) in human ApoA1 transgenic mice.
Synergistic increase in fecal cholesterol excretion by the combination of PPARα and LXR agonists in SV/129 wild-type or PPARα-humanized mice (A) and human ApoA1 transgenic mice (B and C).J Pharmacol Exp Ther.2008 Dec;327(3):716-26. |
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 BMS-687453 lowers serum triglycerides (A) and LDLc (B) in fat-fed hamsters.J Pharmacol Exp Ther.2008 Dec;327(3):716-26.
Liver gene induction occurs at a much lower dose in PPARα-humanized mice compared with mice harboring wild-type (mouse) PPARα.J Pharmacol Exp Ther.2008 Dec;327(3):716-26. |
BMS-711939 lowers serum triglycerides (A) and LDLc (B) in fat-fed hamsters.
Plasma triglyceride lowering correlates with hepatic gene induction.J Pharmacol Exp Ther.2008 Dec;327(3):716-26. |
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