Pemafibrate (3 mg/kg, p.o.) increases plasma h-apoA-I in human apoA-I (h-apoA-I) transgenic mice, and shows higher levels of plasma h-apoA-I than fenofibrate at 300 mg/kg[1]. Pemafibrate (0.03 mg/kg) decreases levels of triglycerides and aspartate aminotransferase (AST) in PEMA-L (db/db) mice. Pemafibrate (0.1 mg/kg) not only shows such effects but increases liver weight in PEMA-H (db/db) mice. Pemafibrate enhances the pathogenesis in a rodent model of nonalcoholic steatohepatitis (NASH). Pemafibrate significantlly reduces the grade of hepatocyte ballooning in PEMA-H mice. Furthermore, Pemafibrate modulates lipid turnover and induces uncoupling protein 3 (UCP 3) expression in the liver[2]. Pemafibrate (K-877, 0.0005%) contained in high-fat diet (HFD) inhibits the body weight gain in mice. Pemafibrate significantly decreases the abundance of triglyceride (TG)-rich lipoproteins, including remnants, in postprandial plasma of mice. Pemafibrate also decreases intestinal mRNA expression of ApoB and Npc1l1[3].

The embryonic rat cardiomyocyte-derived cell line H9c2 was cultured in high-glucose DMEM supplemented with 10% FBS, 100 U/ml penicillin and 100 µg/ml streptomycin at 37˚C in a humidified incubator with 5% CO2. The cells (1x106 cells/well) were seeded into 6-well plates. Prior to the experiments, the cells were starved in 1% FBS-supplemented low glucose DMEM for 24 h and divided into the following groups: i) Low glucose (control; final concentration, 5.5 mmol/l); ii) high glucose (HG; final concentration, 33 mmol/l); iii) HG + hypoxia/reoxygenation (HG + H/R); and iv) HG + H/R + 50 nmol/l Pemafibrate. Briefly, when the cells reached 60% confluence, they were pre-treated with control or HG media for 48 h. Subsequently, the H/R model was induced by culturing the cells for 6 h in hypoxic conditions (95% N2 and 5% CO2) with 1% FBS-DMEM, followed by 4 h of reoxygenation in normal culture conditions. Pemafibrate was dissolved in DMSO (203.85 mmol/l) before being added to media.https://pmc.ncbi.nlm.nih.gov/articles/PMC7903427/

[1]. Design and synthesis of highly potent and selective human\nperoxisome proliferator-activated receptor alpha agonists. Bioorg Med\nChem Lett. 2007 Aug 15;17(16):4689-93.

[2]. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017 Feb 14:7:42477.

[3]. A Novel Selective PPAR\u03b1 Modulator (SPPARM\u03b1), K-877\n(Pemafibrate), Attenuates Postprandial Hypertriglyceridemia in Mice. J\nAtheroscler Thromb. 2018 Feb 1;25(2):142-152.

Pemafibrate belongs to the 1,3-benzoxazole class of compounds, with the structure 1,3-benzoxazole-2-amine, wherein the amino hydrogen is replaced by 3-[(1R)-1-carboxypropoxy]benzyl and 3-(4-methoxyphenoxy)propyl. It is a selective peroxisome proliferator-activated receptor (PPAR)-α agonist used to treat hyperlipidemia. It has dual effects as a PPARα agonist, lipid-lowering agent, and hepatoprotective agent. It belongs to the 1,3-benzoxazole, methoxybenzene, monocarboxylic acid, aromatic amine, and tertiary amine classes of compounds. Pemafibrate is currently being investigated in the clinical trial NCT03350165 (Study of Pemafibrate in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)). Drug Indications: Prevention of cardiovascular events in patients with hypertriglyceridemia, and treatment of hypertriglyceridemia.

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The combination of benzoxazole, phenoxyalkyl side chain and phenoxybutyric acid has been identified as a potent and selective human peroxisome proliferator-activated receptor α (PPARα) agonist. This article describes the synthesis, structure-activity relationship (SAR) studies and in vivo activity of representative compounds. [1]

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The efficacy of peroxisome proliferator-activated receptor α agonists (e.g. fibrates) in human non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is unclear. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that maximizes the beneficial effects of currently used fibrates while minimizing their adverse effects. In a phase II study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidemia. In this study, we first investigated the effects of pemafibrate in a rodent model of NASH. In a diet-induced rodent model of NASH, we evaluated the efficacy of pemafibrate versus fenofibrate. Pemafibrate and fenofibrate both improve the pathological conditions of obesity, dyslipidemia, liver dysfunction and NASH. Pemafibrate significantly improves insulin resistance and increases energy expenditure. To investigate the effects of pemafibrate, we analyzed the expression and protein levels of genes involved in lipid metabolism and analyzed the expression of uncoupled protein 3 (UCP3). Pemafibrate stimulates lipid turnover in the liver and upregulates the expression of UCP3. Pemafibrate significantly increases the levels of acyl-CoA oxidase 1 and UCP3 proteins. Pemafibrate may improve the pathogenesis of non-alcoholic steatohepatitis (NASH) by regulating lipid turnover and energy metabolism in the liver. Pemafibrate is a promising drug for the treatment of NAFLD/NASH. [2] Objective: Fasting and postprandial hypertriglyceridemia (PHTG) is caused by the accumulation of triglyceride (TG)-rich lipoproteins and their residues, which have atherogenic effects. Fibrates can improve fasting and postprandial hypertriglyceridemia; however, clinically, there is a need to reduce residual levels to improve health outcomes. In this study, we investigated the effects of a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) K-877 (Pemafibrate) on PHTG and residual metabolism. Methods: Male C57BL/6J mice from 8 to 12 weeks of age were fed a high-fat diet (HFD), a high-fat diet containing 0.0005% K-877, or a high-fat diet containing 0.05% fenofibrate, respectively. After 4 weeks of feeding, we measured plasma levels of triglycerides (TG), free fatty acids (FFA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (apo) B-48/B-100 after fasting and oral fat loading (OFL). Plasma lipoprotein profiles of mice after oral administration of fat emulsion (OFL) were evaluated using high-performance liquid chromatography (HPLC), and fasting lipoprotein lipase (LPL) activity was compared. Results: Both K-877 and fenofibrate inhibited weight gain, fasting and postprandial triglyceride (TG) levels, and enhanced LPL activity in high-fat diet (HFD) mice. HPLC analysis showed that K-877 and fenofibrate significantly reduced the abundance of TG-rich lipoproteins (including residual lipoproteins) in postprandial plasma. Both K-877 and fenofibrate reduced the mRNA expression of intestinal ApoB and Npc1l1; however, fenofibrate increased the expression of Srebp1c and Mttp in the liver, while K-877 had no such effect. K-877 reduced the mRNA expression of apoC-3 in the liver, while fenofibrate had no such effect. Conclusion: K-877 may be more effective than fenofibrate in alleviating postprandial hyperglycemia (PHTG) by inhibiting the increase of postprandial chylomicrons and the accumulation of chylomicron residues. [3] Diabetes accelerates myocardial cell damage caused by hyperglycemia susceptibility. Activation of peroxisome proliferator-activated receptor α (PPARα) can reduce ischemia-reperfusion (IR) injury in non-diabetic animals. Therefore, this study hypothesized that pemafibrate may have a protective effect on myocardium in vivo and in vitro. This study used a type 1 diabetic (T1DM) rat model and H9c2 cells exposed to high glucose, hypoxia and reoxygenation. The rat model and cells were then treated with pemafibrate. In the T1DM rat model, pemafibrate enhanced the expression of PPARα in the diabetic myocardial ischemia-reperfusion injury (D-IRI) group compared with the untreated group. The infarct area was reduced in the D-IRI group after pemafibrate treatment compared with the untreated group. Pemafibrate partially restored the mitochondrial structure and myofibril damage in the D-IRI group. Furthermore, to evaluate the mechanism of action of pemafibrate in treating diabetic myocardial ischemia-reperfusion injury, an in vitro model was established. Compared with the control group or the high glucose treatment group, the PPARα protein expression level was reduced in the high glucose combined with hypoxia/reoxygenation (H/R) group. Compared with the high glucose combined with H/R group, pemafibrate treatment significantly increased ATP and superoxide dismutase levels and reduced mitochondrial reactive oxygen species and malondialdehyde levels. In addition, pemafibrate inhibited the expression of cytochrome c and cleaved caspase-3, indicating their involvement in the regulation of mitochondrial apoptosis. Pemafibrate also reduced nuclear factor-κB (NF-κB) expression, and NF-κB activation reversed the in vitro protective effect of pemafibrate against diabetic myocardial ischemia-reperfusion injury. In summary, these results suggest that pemafibrate may protect the myocardium of type 1 diabetic rats from ischemia-reperfusion injury by inhibiting the activation of PPARα through the NF-κB signaling pathway. https://pmc.ncbi.nlm.nih.gov/articles/PMC7903427/

C28H29N2NAO6

512.529438734055

512.192

C, 65.62; H, 5.70; N, 5.47; Na, 4.49; O, 18.73

950644-31-2

950644-31-2 (sodium); 848258-31-1 (racemate); 848259-27-8 (free acid);

91826962

Typically exists as solid at room temperature

0

8

13

37

665

1

CC[C@H](C(=O)[O-])OC1=CC=CC(=C1)CN(CCCOC2=CC=C(C=C2)OC)C3=NC4=CC=CC=C4O3.[Na+]

JSNXVHCVJMDNKW-VQIWEWKSSA-M

InChI=1S/C28H30N2O6.Na/c1-3-25(27(31)32)35-23-9-6-8-20(18-23)19-30(28-29-24-10-4-5-11-26(24)36-28)16-7-17-34-22-14-12-21(33-2)13-15-22/h4-6,8-15,18,25H,3,7,16-17,19H2,1-2H3,(H,31,32)/q+1/p-1/t25-/m1./s1

Sodium (2R)-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoate

K-877 sodium; (R)-K13675K877; (R)-K 13675; K 877; Pemafibrate sodium; Pemafibrate sodium, (+)-; 950644-31-2; UNII-321L8P020Q; 321L8P020Q; Butanoic acid, 2-(3-((2-benzoxazolyl(3-(4-methoxyphenoxy)propyl)amino)methyl)phenoxy)-, sodium salt (1:1), (2R)-; Q27256115; sodium;(2R)-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoate (R) K-13675; Pemafibrate sodium; (R)-K 13675; Parmodia

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.)