| Description | Seladelpar (MBX 8025) has been used in trials studying the treatment of Hyperlipidemia. |
| In vitro | Seladelpar (MBX-8025) is an orally active, potent (2 nM), and specific (>750-fold and >2500-fold compared with PPAR-α or PPAR-γ receptors, respectively) PPAR-δ agonist which is developed as a lipid-altering agent[1]. Seladelpar is a potent, and selective PPAR-δ agonist (50% effect concentration human PPAR-δ=2 nM, PPAR-α=1,600 nM) that demonstrates favorable effects on insulin resistance, diabetes, and atherogenic dyslipidemia[2]. |
| In vivo | Female Alms1突变(female foz/foz)小鼠及其野生型近亲从断乳后开始接受高脂饮食16周，之后按照组别(n=8-12)随机分配，通过灌胃给予Seladelpar(10 mg/kg)或载体(1% methylcellulose)处理8周。尽管对体重影响最小，Seladelpar在foz/foz小鼠中能够正常化高血糖、高胰岛素血症以及葡萄糖处置。载体处理的foz/foz小鼠，血清谷丙转氨酶水平在300-600 U/L之间；Seladelpar使谷丙转氨酶降低50%。此外，Seladelpar正常化血清脂质以及肝脏中自由胆固醇和其他在载体处理的foz/foz与野生型小鼠间增加的脂毒性脂质水平。这消除了肝细胞空泡化和凋亡，显著减少脂肪变性和肝炎症，并改善肝纤维化。载体处理的foz/foz小鼠中，非酒精性脂肪性肝疾病活动评分平均为6.9，表明非酒精性脂肪性肝炎(NASH)；Seladelpar在所有foz/foz小鼠中逆转NASH(非酒精性脂肪性肝疾病活动评分3.13)。在高脂饮食喂养的Wt小鼠中，Seladelpar通过约18%(P<0.05)减轻体重。相比之下，在高脂饮食喂养的foz/foz小鼠中，Seladelpar对体重的影响最小。这些动物在16周后发展为严重高血糖、高胰岛素血症以及全身胰岛素抵抗(P<0.05)；Seladelpar显著改善这些指标(P<0.05)。腹腔注射葡萄糖后，载体处理的foz/foz小鼠血糖水平达到~32 mM，而Seladelpar处理的foz/foz小鼠约为~14 mM(P<0.05)；相应地，Seladelpar处理的foz/foz小鼠血糖消失曲线下面积较低(P<0.05)。Seladelpar在高脂饮食喂养的Wt小鼠中对葡萄糖处理产生比例相似的效果(P<0.05)[2]。 |
| Animal experiments | From weaning (week 4), Alms1 mutant (foz/foz) NOD.B10 mice or Wt littermates (female mice in both groups) are fed an atherogenic diet (23% fat, 0.2% cholesterol and 45% simple carbohydrate; 4.78 kcal/g digestible energy) ad libitum for 16 weeks, after which groups are randomized (n=8-12 mice/group) to once-a-day oral administration (by gavage) for 8 weeks of Seladelpar (10 mg/kg in 1% methylcellulose) or vehicle (controls). Animals are housed under 12-hour light/dark cycle and constant temperature of 22°C and receive maximal humane care[2]. |
| Target activity | PPARδ:2 nM (EC50), PPARα:1600 nM (EC50) |
| Synonyms | MBX 8025 |
| molecular weight | 444.46 |
| Molecular formula | C21H23F3O5S |
| CAS | 851528-79-5 |
| Storage | store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year |
| Solubility | DMSO: 10 mg/mL (22.5 mM) |
| References | 1. Bays HE, et al. 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. Haczeyni F, et al. 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. |