CAY10444
(Synonyms: BML-241) 目录号 : GC18757CAY10444是一种鞘氨醇-1-磷酸受体3（S1P3）拮抗剂。CAY10444能够抑制表达人类S1P3的CHO细胞中由S1P引起的钙离子释放（IC50值为11.6μM）。
Cas No.:298186-80-8
Sample solution is provided at 25 µL, 10mM.
CAY10444 is a sphingosine-1-phosphate receptor 3 (S1P3) antagonist. CAY10444 can inhibit calcium ion release caused by S1P in CHO cells expressing human S1P3 (IC50 value is 11.6μM) [1-2]. S1P3 plays a crucial role in pathological physiological processes related to inflammation, cell proliferation, cell migration, tumor invasion and metastasis, ischemia-reperfusion, tissue fibrosis, and vascular tension [3]. CAY10444 can be used for the research of therapeutic targets for ischemia/reperfusion injury [4].
In vitro, CAY10444 (17.4μM; 15min) treatment significantly inhibited the activity of Na/K-ATPase in HepG2 cells [5]. CAY10444 (5μM; 24h) treatment significantly inhibited the increase in the expression levels of S1PR3, CCL2, TNF-α, and PI3K/AKT signaling pathways in mouse HT22 neurons after S1P administration, and improved neuronal apoptosis [6].
In vivo, CAY10444 (0.5mg/kg/day; 6, 24h, and 48h after ICH (a total of three doses); i.p.) significantly reduced the increased expression levels of S1PR3 and CCL2 in the brain tissue surrounding the hematoma in mice with intracerebral hemorrhage (ICH) model, and simultaneously inhibited the activation of the TNF-α/caspase-3 apoptotic signaling pathway [6]. The dose-dependent administration of CAY10444 (0.1, 0.2, and 0.5mg/kg/day; 24h; i.p.) alleviated the cerebral infarction and neurological deficits induced by tMCAO in mice, and significantly reduced the number of Iba1-immunopositive cells and the number of activated microglia in the ischemic area. [7].
References:
[1] Koide, Y., Hasegawa, T., Takahashi, A., et al. Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships. J. Med. Chem. 45(21), 4629-4638 (2002)
[2] Salomone S, Waeber C. Selectivity and specificity of sphingosine-1-phosphate receptor ligands: caveats and critical thinking in characterizing receptor-mediated effects. Front Pharmacol. 2011;2:9.
[3] Fan X, Liu L, Shi Y, et al. Recent advances of the function of sphingosine 1‐phosphate (S1P) receptor S1P3[J]. Journal of Cellular Physiology, 2021, 236(3): 1564-1578.
[4] Fan X, Chen H, Xu C, et al. Inhibiting sphingosine 1-phosphate receptor subtype 3 attenuates brain damage during ischemia-reperfusion injury by regulating nNOS/NO and oxidative stress[J]. Frontiers in Neuroscience, 2022, 16: 838621.
[5] Al Alam N, Kreydiyyeh S I. FTY720P inhibits hepatic Na+–K+ ATPase via S1PR2 and PGE2[J]. Biochemistry and Cell Biology, 2016, 94(4): 371-377.
[6] Song D, Li M, Zhang L, et al. Sphingosine-1-phosphate receptor 3 promotes neuronal apoptosis via the TNF-α/caspase-3 signaling pathway after acute intracerebral hemorrhage. Mol Cell Neurosci. 2024;131:103979.
[7] Gaire BP, Song MR, Choi JW. Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization. J Neuroinflammation. 2018;15(1):284.
CAY10444是一种鞘氨醇-1-磷酸受体3（S1P3）拮抗剂。CAY10444能够抑制表达人类S1P3的CHO细胞中由S1P引起的钙离子释放（IC50值为11.6μM）[1-2]。S1P3在与炎症、细胞增殖、细胞迁移、肿瘤侵袭和转移、缺血再灌注、组织纤维化和血管张力相关的病理生理过程中起着至关重要的作用 [3]。CAY10444可用于缺血/再灌注损伤的治疗靶点研究 [4]。
在体外，CAY10444（17.4μM; 15min）处理显著抑制了HepG2细胞中Na/K-ATP酶的活性 [5]。CAY10444（5μM; 24h）处理显著抑制了施用S1P后的小鼠HT22神经元中S1PR3、CCL2、TNF-α 和PI3K/AKT信号通路的表达水平的增加，并且改善了神经元的凋亡 [6]。
在体内，CAY10444（0.5mg/kg/day; 6, 24h, and 48h after ICH (a total of three doses); i.p.）显著降低了脑内出血模型（ICH）小鼠血肿周围脑组织中S1PR3和CCL2的表达水平的上升，同时抑制了TNF-α/caspase-3凋亡信号的激活 [6]。CAY10444（0.1. 0.2, and 0.5mg/kg/day; 24h; i.p.）剂量依赖性减轻了tMCAO诱导的小鼠脑梗死和神经功能缺陷，并显著减少了Iba1免疫阳性细胞的数量和缺血区域中活化的小胶质细胞数量 [7]。
| Cell experiment [1]: | |
Cell lines | HT22 cells |
Preparation Method | Immortalized HT22 mouse hippocampal neurons (HT22) were obtained from Newgainbio Company. Three to four days after the initial coculture, S1P (1, 3, 5, or 10μM) and CAY10444 (5μM) were added to the culture medium. The control group was treated with the same amount of dimethylsulfoxide (DMSO), a solvent for the drug. The cells were collected 24h later, and RIPA buffer supplemented with PMSF and a protein phosphatase inhibitor was added to lyse the cells. After the proteins were extracted, the protein expression of S1PR3, CCL2, TNF-α, c-caspase-3, PI3K, p-PI3K, AKT, p-AKT and GAPDH was detected. |
Reaction Conditions | 5μM; 24h |
Applications | CAY10444 significantly inhibited the increase in the expression levels of S1PR3, CCL2, TNF-α and the PI3K/AKT signaling pathway in HT22 neurons after the administration of S1P, and also significantly improved neuronal apoptosis. |
| Animal experiment [2]: | |
Animal models | ICR mice |
Preparation Method | Establish a mouse model of transient middle cerebral artery occlusion and reperfusion (tMCAO) to investigate the pathogenic role of S1P3 in transient focal cerebral ischemia. The mice were anesthetized with isoflurane in a N2O:O2 (3:1) mixture, and the right common carotid artery was isolated through a ventral neck incision. A silicone-coated 5-0 monofilament was introduced to the internal carotid artery from carotid bifurcation and advanced to occlude the middle cerebral artery (MCA). After 90min of MCAO, the filament was withdrawn to allow complete reperfusion of the cerebral area. CAY10444 was dissolved in 1:1 mixture of chremophore EL and 100% ethanol, diluted in water, and injected intraperitoneally to mice at 0.1, 0.2, and 0.5mg/kg at the time of reperfusion. For the tMCAO group, equal volumes of the vehicle were injected. After 24 hours of tMCAO, the mice were sacrificed and brain samples were taken.Then assess brain damage such as brain infarction, neurological functional deficit, and neural cell death. |
Dosage form | 0.1. 0.2, and 0.5mg/kg/day; 24h; i.p. |
Applications | The dose-dependent administration of CAY10444 alleviated the cerebral infarction and neurological deficits induced by tMCAO in mice, and significantly reduced the number of Iba1-immunopositive cells and the number of activated microglia in the ischemic area. |
References: | |
| Cas No. | 298186-80-8 | SDF | |
| 别名 | BML-241 | ||
| 化学名 | 2-undecyl-thiazolidine-4-carboxylic acid | ||
| Canonical SMILES | [H]N1C(CCCCCCCCCCC)SC[C@H]1C(O)=O | ||
| 分子式 | C15H29NO2S | 分子量 | 287.5 |
| 溶解度 | 0.5mg/mL in DMF | 储存条件 | Store at -20°C |
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| 1 mM | 3.4783 mL | 17.3913 mL | 34.7826 mL |
| 5 mM | 695.7 μL | 3.4783 mL | 6.9565 mL |
| 10 mM | 347.8 μL | 1.7391 mL | 3.4783 mL |
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