PPAR-δ (EC50 = 2 μM); PPAR-α (EC50 = 1600 μM)

Mice: Atherogenic diet (23 percent fat, 0.2 percent cholesterol, and 45 percent simple carbohydrate; 4.78 kcal/g digestible energy) is fed ad libitum to Alms1 mutant (foz/foz) NOD.B10 mice or Wt littermates (female mice in both groups) from the time of weaning (week 4). Following this, groups are randomized (n=8–12 mice/group) to once-daily oral administration (by gavage) of Seladelpar (10 mg/kg in 1% methylcellulose) or vehicle (controls) for 8 weeks. Animals are kept in housing with a 12-hour light/dark cycle, a constant temperature of 22°C, and the highest level of humane treatment[2].

Absorption
After a single dose, systemic exposure to celardpa increases proportionally with increasing dose, from 2 mg (0.2 times the recommended dose) to 15 mg (1.5 times the recommended dose), and then increases dose-proportionally with higher doses. When the dose increases from 10 mg to 200 mg (20 times the recommended dose), the mean Cmax and mean AUC of celardpa increase by 70-fold and 27-fold, respectively. After once-daily administration, celardpa reaches steady state on day 4, with an AUC increase of less than 30%. In patients with primary biliary cholangitis (PBC), after reaching steady state with once-daily administration of 10 mg celardpa, the mean (standard deviation) Cmax and AUC are 103 (29.3) ng/mL and 902 (238) ng·h/mL, respectively. The median time to peak concentration (Tmax) of celardpa is 1.5 hours. No clinically significant differences in the pharmacokinetics of seladelpar were observed in healthy subjects after ingestion of a high-fat meal.
Excretion Route
Seladelpar is primarily excreted in the urine as a metabolite. Following a single oral dose of 10 mg of radiolabeled seladelpar in humans, approximately 73.4% of the dose is excreted in the urine (less than 0.01% unchanged drug) and 19.5% is excreted in the feces (2.02% unchanged drug). Animal studies suggest that seladelpar may be excreted in the bile.
Volume of Distribution
The steady-state apparent volume of distribution of seladelpar is approximately 133.2 L.
Clearance
The apparent oral clearance of seladelpar is 12 L/h.
Protein Binding
The plasma protein binding of seladelpar is greater than 99%.
Metabolism/Metabolites
Seladelpar is primarily metabolized in vitro via CYP2C9, with minor metabolism via CYP2C8 and CYP3A4, yielding three major metabolites: seladelpar sulfoxide (M1), desethylseladelpar (M2), and desethylseladelpar sulfoxide (M3). The AUC ratios of the metabolites to the parent drug for M1, M2, and M3 are 0.36, 2.32, and 0.63, respectively. The median Tmax for the metabolites are 10 hours for M1, and 4 hours for both M2 and M3. All major metabolites are pharmacologically inactive.
Biological Half-Life
In healthy subjects, the mean elimination half-life of seladelpar is 6 hours after a single 10 mg dose. In patients with PBC, the half-life of seladelpar ranges from 3.8 to 6.7 hours.

Hepatotoxicity
In pre-registration clinical trials, seladelpar was found to significantly reduce serum transaminase and alkaline phosphatase levels in most patients with primary biliary cholangitis (PBC). However, in an initial dose-exploration study of PBC patients, 3 out of 25 subjects (taking 50 mg and 200 mg daily) experienced transient increases in ALT and AST levels exceeding the upper limit of normal (ULN) by more than 5 times, while this did not occur in the placebo group. These increases occurred over several months of treatment and returned rapidly upon discontinuation of the drug. Notably, alkaline phosphatase levels decreased significantly during the ALT elevation and returned to pre-treatment levels quickly after discontinuation of the drug. In contrast, in subsequent clinical trials of seladelpar at a daily dose of 10 mg in PBC patients, ALT elevations exceeding 5 times the ULN were rare, occurred randomly, and were generally attributed to other causes. In a large, pre-registered, randomized, placebo-controlled trial, 2 out of 128 patients (1.6%) receiving seladelpar discontinued treatment due to abnormal liver function, compared to 2 out of 65 patients (3.1%) receiving placebo. No clinically significant liver injury caused by seladelpar has been reported in several small clinical trials. However, clinical experience with seladelpar is generally limited, and rare drug-induced liver injury is known to occur with other PPAR agonists such as fenofibrate, bezafibrate, pioglitazone, and rosiglitazone. In long-term extended studies, a small number of patients taking seladelpar experienced decompensation and jaundice, but all of these cases occurred in patients with pre-existing cirrhosis and were explained as being due to disease progression and unrelated to treatment. However, seladelpar and other PPAR agonists are not recommended for patients with advanced or decompensated cirrhosis, and regular monitoring of liver function is advised during treatment. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury).

[1]. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin Endocrinol Metab. 2011 Sep;96(9):2889-97.

[2]. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol Commun. 2017 Jul 31;1(7):663-674.

Seradepar (MBX-8025) has been used in clinical trials for the treatment of hyperlipidemia.

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Drug Indications
Treatment of primary biliary cholangitis
Mechanism of Action
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily, which includes three members: PPAR-α, PPAR-δ, and PPAR-γ. Each PPAR plays a role in maintaining energy homeostasis and metabolic functions, such as fatty acid metabolism, bile acid synthesis, and adipocyte differentiation. In chronic liver diseases such as primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH), altered bile acid composition and elevated systemic bile acid levels are observed. Seradepar is a PPAR-δ agonist; however, the mechanism by which seradepar exerts its therapeutic effect in patients with PBC is not fully understood. Potential pharmacological activities related to therapeutic efficacy include inhibition of bile acid synthesis through activation of PPARδ. Published studies have shown that celadepa activation of PPARδ can reduce bile acid synthesis by inducing fibroblast growth factor 21 (FGF21), thereby activating the c-Jun N-terminal kinase (JNK) signaling pathway. This effect subsequently downregulates CYP7A1, a key enzyme in cholesterol-to-bile acid synthesis. Studies have shown that celadepa's inhibitory effect on bile acid synthesis is independent of the farnesoid X receptor (FXR) pathway, another molecular pathway regulating hepatic bile acid synthesis.
Pharmacodynamics
Celadepa can reduce total bile acid levels and decrease bile acid synthesis in patients with primary biliary cholangitis (PBC). Studies have shown that elevated bile acid concentrations in hepatobiliary diseases, including primary biliary cholangitis (PBC), can lead to elevated alkaline phosphatase (ALP) levels. In PBC patients treated with 10 mg seladelpar once daily, a significant reduction in mean ALP levels from baseline was observed one month after treatment compared to the placebo group, and the lower ALP levels typically persisted until month 12. In another study, a dose-dependent reduction in mean ALP levels was also observed in PBC patients treated with 2 mg, 5 mg, or 10 mg seladelpar once daily. Seladelpar is a peroxisome proliferator-activated receptor (PPAR)-δ agonist. Seladelpar is a single enantiomer of the R configuration. On August 14, 2024, the FDA granted accelerated approval to seladelpar for the treatment of primary biliary cholangitis, a disease associated with abnormal bile acid metabolism. Seladelpar works by blocking bile acid synthesis.
Serradepa is an oral peroxisome proliferator-activated receptor delta (PPARδ) agonist used in combination with ursodeoxycholic acid to treat primary biliary cholangitis (PBC). Rarely, elevated liver enzymes have been observed during serradepa treatment, but there is no conclusive evidence linking them to clinically significant liver damage with jaundice.
Serradepa is an orally bioavailable peroxisome proliferator-activated receptor (PPAR)-δ (PPARd) agonist whose activity is reduced by bile acids. After oral administration, serradepa targets, binds to, and activates PPARd in the liver. This induces the expression of fibroblast growth factor 21 (FGF21), which downregulates the activity of CYP7A1, a key enzyme in the synthesis of bile acids from cholesterol. By reducing CYP7A1 expression, bile acid synthesis is reduced. This may alleviate inflammation and scarring associated with primary biliary cholangitis (PBC). SELADELPAR is a small molecule drug that has completed Phase IV clinical trials (covering all indications) and was first approved in 2024 for the treatment of biliary cirrhosis. It also has 6 investigational indications.

C27H37F3N2O7S

590.652097463608

590.227357

C, 54.90; H, 6.31; F, 9.65; N, 4.74; O, 18.96; S, 5.43

928821-41-4

851528-79-5; 928821-40-3 (lysine hydrate); 3026272-26-1 (sodium); 928821-41-4 (lysine)

15983987

White to off-white solid powder

4

13

16

40

617

2

S(C1C=CC(=C(C)C=1)OCC(=O)O)C[C@@H](COC1C=CC(C(F)(F)F)=CC=1)OCC.OC([C@H](CCCCN)N)=O

IOIAOZMQFNHRKR-FFHLUDTASA-N

InChI=1S/C21H23F3O5S.C6H14N2O2/c1-3-27-17(11-28-16-6-4-15(5-7-16)21(22,23)24)13-30-18-8-9-19(14(2)10-18)29-12-20(25)26;7-4-2-1-3-5(8)6(9)10/h4-10,17H,3,11-13H2,1-2H3,(H,25,26);5H,1-4,7-8H2,(H,9,10)/t17-;5-/m10/s1

(2S)-2,6-diaminohexanoic acid;2-[4-[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid

MBX-8025 (lysine); 928821-41-4; UNII-75US2513Z8; MBX-8025 LYSINE ANHYDROUS; 75US2513Z8; MBX-8025 (lysine);

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.)