Seladelpar (formerly MBX-8025 and RWJ-800025) is a novel, orally bioactive and selective peroxisome proliferator-activated receptor (PPAR)-δ receptor agonist with anti-cholestatic effects. Its EC50 of 2 nM indicates that it inhibits PPAR-δ. Seladelpar acts as an anti-inflammatory and anti-fibrotic agent through PPAR-delta agonism. Additionally, this method raises lipid metabolism and lowers bile acids. Phase 3 clinical trials are currently being conducted on selegelapar. Treatment for dyslipidemia, metabolic syndrome, type 2 diabetes, and non-alcoholic steatohepatitis may involve the use of selazelpar.

Physicochemical Properties

Molecular Formula	C21H23F3O5S
Molecular Weight	444.464535951614
Exact Mass	444.121
Elemental Analysis	C, 56.75; H, 5.22; F, 12.82; O, 18.00; S, 7.21
CAS #	851528-79-5
Related CAS #	Seladelpar sodium salt
PubChem CID	11236126
Appearance	Colorless to light yellow liquid
Density	1.3±0.1 g/cm3
Boiling Point	557.5±50.0 °C at 760 mmHg
Flash Point	291.0±30.1 °C
Vapour Pressure	0.0±1.6 mmHg at 25°C
Index of Refraction	1.554
LogP	6.16
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	11
Heavy Atom Count	30
Complexity	511
Defined Atom Stereocenter Count	1
SMILES	O(C1C=CC(SC[C@H](OCC)COC2C=CC(C(F)(F)F)=CC=2)=CC=1C)CC(=O)O
InChi Key	JWHYSEDOYMYMNM-QGZVFWFLSA-N
InChi Code	InChI=1S/C21H23F3O5S/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/h4-10,17H,3,11-13H2,1-2H3,(H,25,26)/t17-/m1/s1
Chemical Name	2-[4-[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid
Synonyms	MBX-8025; RWJ800025; MBX 8025; RWJ 800025; MBX8025; RWJ-800025
HS Tariff Code	2934.99.9001
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)

Biological Activity

Targets	PPAR-δ (EC50 = 2 μM); PPAR-α (EC50 = 1600 μM)
ln Vitro	Seladelpar (MBX-8025) is a PPAR-δ agonist that is being developed as a lipid-altering agent. It is orally active, potent (2 nM), and specific (>750-fold and >2500-fold compared with PPAR-α or PPAR-γ receptors, respectively)[1]. With a 50% effect concentration of human PPAR-δ = 2 nM and PPAR-α = 1,600 nM, seladelpar is a potent and selective PPAR-δ agonist that shows positive effects on atherogenic dyslipidemia, insulin resistance, and diabetes[2].
ln Vivo	Following weaning, wild-type littermates and female Alms1 mutant (foz/foz) mice are given an atherogenic diet for 16 weeks.After that, groups (n=8–12) are randomized to receive either vehicle (1% methylcellulose) or Seladelpar (10 mg/kg) by gavage for an additional 8 weeks. Seladelpar normalizes glucose disposal, hyperglycemia, and hyperinsulinemia in foz/foz mice while hardly changing body weight. In mice treated with a vehicle, the serum level of alanine aminotransferase ranges from 300 to 600 U/L; Seladelpar reduces this level by 50%. Furthermore, Seladelpar restores normalcy to serum lipid levels, hepatic levels of free cholesterol, and other lipotoxic lipids that exhibit elevation in vehicle-treated foz/foz mice relative to wild-type mice. This significantly reduced steatosis and liver inflammation, eliminated hepatocyte ballooning and apoptosis, and improved liver fibrosis. The mean nonalcoholic fatty liver disease activity score in vehicle-treated foz/foz mice is 6.9, indicating nonalcoholic steatohepatitis (NASH); in all foz/foz mice, selegilegpar reverses NASH (nonalcoholic fatty liver disease activity score 3.13). When administered to Wt mice fed an atherogenic diet, Seladelpar reduces body weight by approximately 18% (P<0.05). On the other hand, Seladelpar has little effect on body weight in mice fed an atherogenic diet (foz/foz). After sixteen weeks (P<0.05), these animals develop severe hyperglycemia, hyperinsulinemia, and whole-body insulin resistance; selegilapar remarkably improves these indices (P<0.05). Following intraperitoneal injection of glucose, blood glucose levels in vehicle-treated mice reach approximately 32 mM, while in Seladelpar-treated foz/foz mice they reach approximately 14 mM (P<0.05); Seladelpar-treated foz/foz mice also have a lower area under the blood glucose disappearance curve (P<0.05). Seladelpar has a comparable effect (P<0.05) on glucose handling in Wt mice fed an atherogenic diet[2].
Animal Protocol	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].
References	[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.
Additional Infomation	Seladelpar (MBX-8025) has been used in trials studying the treatment of Hyperlipidemia. Drug Indication Treatment of primary biliary cholangitis

Solubility Data

Solubility (In Vitro)

DMSO: ~100 mg/mL (~225 mM)

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) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2499 mL	11.2496 mL	22.4992 mL
	5 mM	0.4500 mL	2.2499 mL	4.4998 mL
	10 mM	0.2250 mL	1.1250 mL	2.2499 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.