BAF312 (Siponimod)是一种选择性、口服有效的sphingosine-1-phosphate (S1P)受体激动剂，对S1P1、S1P4和S1P5受体的EC50值分别为0.39nM、750nM和0.98nM。
Cas No.:1230487-00-9
Sample solution is provided at 25 µL, 10mM.
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BAF312 (Siponimod) is a selective and orally active sphingosine-1-phosphate (S1P) receptor agonist, with the EC50 values of 0.39, 750, and 0.98nM for S1P1, S1P4, and S1P5 receptors, respectively [1]. BAF312 maintains the stability of the endothelial barrier by regulating the S1P receptors in microglia and enhances the endothelial barrier function of the blood-brain barrier (BBB)[2]. BAF312 has been widely used to improve the neurological function, repair GABAergic deficits in the striatum, and alleviate inflammatory responses in experimental autoimmune encephalomyelitis animal models [3].
In vitro, BAF312 treatment for 48 hours significantly inhibited the viability of mouse bone marrow macrophages (BMM), with an IC50 value of 45.38µM[4]. 1µM BAF312 treatment for 30 minutes significantly increased the phosphorylation of ERK and AKT in mouse astrocytes and induced the internalization of S1P1[5]. Treatment with 20µM BAF312 for 72 hours inhibited the G1-S phase transition of U118MG cells, significantly upregulated the expression level of pro-apoptotic protein Bax, and downregulated the expression level of anti-apoptotic protein Bcl-2, thereby inducing cell apoptosis[6].
In vivo, BAF312 treatment via oral administration at a dose of 10mg/kg/day for 7 days can protect the structure and function of the inner layer of the retina in mice from the damage caused by acute excitotoxicity of N-methyl-D-aspartate (NMDA) and diminish NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) [7]. For three consecutive days, a daily intraperitoneal injection of 0.3mg/kg dose of BAF312 was administered, which significantly reduced brain edema in the experimental mouse model of intracerebral hemorrhage (ICH), increased survival rate, and alleviated the sensory-motor dysfunction caused by ICH[8].
References:
[1] Gergely P, Nuesslein‐Hildesheim B, Guerini D, et al. The selective sphingosine 1‐phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species‐specific effects on heart rate[J]. British journal of pharmacology, 2012, 167(5): 1035-1047.
[2] Spampinato S F, Costantino G, Merlo S, et al. Microglia contributes to baf-312 effects on blood–brain barrier stability[J]. Biomolecules, 2022, 12(9): 1174.
[3] Gentile A, Musella A, Bullitta S, et al. Effects of siponimod (BAF312) on inflammation-driven synaptopathy in experimental multiple sclerosis (P5. 311)[J]. Neurology, 2016, 86(16_supplement): P5. 311.
[4] Hu S, Hu Y, Tan Z, et al. Repurposing the multiple sclerosis drug Siponimod for osteoporosis treatment[J]. European Journal of Pharmacology, 2024, 974: 176630.
[5] O’Sullivan C, Schubart A, Mir A K, et al. The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures[J]. Journal of Neuroinflammation, 2016, 13(1): 31.
[6] Qin Q, Zhou Y, Feng M, et al. BAF312 Inhibits the Growth of Glioma and Promotes the Normalization of Tumor Blood Vessels[J]. The FASEB Journal, 2025, 39(16): e70941.
[7] Basavarajappa D, Gupta V, Chitranshi N, et al. Anti-inflammatory effects of siponimod in a mouse model of excitotoxicity-induced retinal injury[J]. Molecular Neurobiology, 2023, 60(12): 7222-7237.
[8] Bobinger T, Manaenko A, Burkardt P, et al. Siponimod (BAF-312) attenuates perihemorrhagic edema and improves survival in experimental intracerebral hemorrhage[J]. Stroke, 2019, 50(11): 3246-3254.
BAF312 (Siponimod)是一种选择性、口服有效的sphingosine-1-phosphate (S1P)受体激动剂，对S1P1、S1P4和S1P5受体的EC50值分别为0.39nM、750nM和0.98nM[1]。BAF312通过调节小胶质细胞中的S1P受体来维持内皮屏障的稳定性，并增强血脑屏障（BBB）的内皮屏障功能[2]。BAF312已被广泛用于改善实验性自身免疫性脑脊髓炎动物模型的神经功能，修复纹状体中的GABA能缺陷，并减轻炎症反应[3]。
在体外，BAF312处理48小时显著抑制了小鼠骨髓巨噬细胞的活力，IC50值为45.38µM[4]。1µM的BAF312处理小鼠星形胶质细胞30分钟，显著增加了ERK和AKT的磷酸化，并诱导了S1P1的内化[5]。用20µM的BAF312处理U118MG细胞72小时，抑制了细胞G1-S期转变，显著上调了促凋亡蛋白Bax的表达水平，并下调了抗凋亡蛋白Bcl-2的表达水平，从而诱导细胞凋亡[6]。
在体内，每日口服10mg/kg剂量的BAF312，连续7天，可保护小鼠视网膜内层结构和功能免受N-methyl-D-aspartate (NMDA)急性兴奋性毒性的损伤，并减少NMDA诱导的NLRP3炎症小体活化和神经毒性诱导型一氧化氮合酶(iNOS)的上调[7]。连续三天每日腹腔注射0.3mg/kg剂量的BAF312，可显著减轻实验性脑出血（ICH）小鼠模型的脑水肿，提高存活率，并减轻ICH引起的感觉运动功能障碍[8]。
| Cell experiment [1]: | |
Cell lines | Mouse Bone marrow macrophages (BMMs) |
Preparation Method | BMMs were seeded into 96-well plates at a density of 6000 cells per well at 37°C for 24h to allow adherence in the α-MEM medium containing 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. Cells were then treated with different concentrations of BAF312 (1, 2.5, 5, 10, 15, 25, 50, 100μM) for 48h, and the viable cell numbers were measured. |
Reaction Conditions | 1, 2.5, 5, 10, 15, 25, 50, 100μM; 48h |
Applications | BAF312 treatment significantly reduced cell proliferation of BMMs in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6 mice |
Preparation Method | Adult male C57BL/6 mice (20-24g) were housed in a specialized animal care facility in a room with constant temperature (25°C), humidity control, and a 12/12h light/dark cycle with free access to food and water. Animal core temperature (37°C) was maintained by a thermostat-controlled warming blanket. Mice were anesthetized with ketamine (100mg/kg) and xylazine (10mg/kg, intraperitoneal injection), then positioned prone in a stereotactic head frame. For preparation of the calvarium, the midline scalp was incised from the nasion to the superior nuchal line. Then, a speed drill device was used to prepare a 1-mm burr hole 0.9mm posterior to the bregma and 2.2mm to the right of the midline. A 26-G needle on a syringe 3.5mm was placed into the right deep cortex/basal ganglia at a rate of 1mm/minute. Collagenase solution (0.075U in 0.5µl saline) was infused at a rate of 0.25µl/minute using an infusion pump. After 10 minutes, the needle was withdrawn, the incision was closed, and the mice were allowed to recover. The sham operation was restricted to needle insertion only. Mice were randomly assigned to different treatment groups: vehicle, BAF312 (0.3mg/kg/day; i.p.) given as a single dosage 30 minutes after the operation or given for 3 consecutive days starting 30 minutes after the operation. The impact of siponimod treatment on perihemorrhagic edema, neurological deficits, and survival in a mouse model of ICH was analyzed. |
Dosage form | 0.3mg/kg/day for 3 days; i.p. |
Applications | BAF312 treatment significantly reduced brain edema, increased survival rate, and improved the neurological deficits in mice with ICH. |
References: | |
| Cas No. | 1230487-00-9 | SDF | |
| 别名 | 辛波莫德; BAF-312 | ||
| 化学名 | 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid | ||
| Canonical SMILES | CCC1=C(C=CC(=C1)C(=NOCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)C)CN4CC(C4)C(=O)O | ||
| 分子式 | C29H35F3N2O3 | 分子量 | 516.6 |
| 溶解度 | ≥ 194.8mg/mL in DMSO | 储存条件 | Store at -20° C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9357 mL | 9.6787 mL | 19.3573 mL |
| 5 mM | 387.1 μL | 1.9357 mL | 3.8715 mL |
| 10 mM | 193.6 μL | 967.9 μL | 1.9357 mL |
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