PF-3845
目录号 : GC16984
PF-3845是一种双靶点抑制剂，可同时靶向脂肪酸酰胺水解酶（FAAH）和可溶性环氧化物水解酶（sEH），对FAAH和sEH的EC50值分别为0.65nM和12000nM。
Cas No.:1196109-52-0
Sample solution is provided at 25 µL, 10mM.
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PF-3845 is a dual inhibitor targeting fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH), with EC50 values of 0.65nM and 12000nM, respectively[1]. PF-3845 covalently inactivates FAAH by carbamylation of the enzyme's serine nucleophile without reacting with other serine hydrolases in vivo[2]. PF-3845 acts as a novel chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis[3].
In vitro, PF-3845 treatment for 48h significantly inhibited the viability of Colo-205 cells with an IC50 value of 51.38μM[4]. Treatment with 10μM PF-3845 for 4 days inhibited receptor activator of nuclear factor kappa B ligand (RANKL)-induced differentiation of mouse bone marrow stromal cells (BMM) into osteoclasts and significantly decreased the mRNA expression of dendritic cell-specific transmembrane protein and cathepsin K in cells[5]. Treatment with 10μM PF-3845 for 18 hours significantly inhibited lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production and reduced inflammatory gene expression in BV2 cells[6].
In vivo, PF-3845 treatment via intraperitoneal injection at a dose of 5mg/kg/day for 14 days significantly restored hippocampal-dependent memory ability and alleviated traumatic brain injury (TBI)-induced anxiety and fine motor deficits in mice with TBI[7]. A single intraperitoneal injection of PF-3845 (5mg/kg) for 60 minutes can improve the plasma corticosterone release and glucose mobilization in rats after acute restraint stress[8].
References:
[1] Kodani S D, Wan D, Wagner K M, et al. Design and potency of dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors[J]. ACS omega, 2018, 3(10): 14076-14086.
[2] Ahn K, Johnson D S, Mileni M, et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain[J]. Chemistry & biology, 2009, 16(4): 411-420.
[3] Wang H, Xu M, Engelhart C A, et al. Rediscovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis[J]. Journal of Biological Chemistry, 2021, 296.
[4] Wasilewski A, Krajewska U, Owczarek K, et al. Fatty acid amide hydrolase (FAAH) inhibitor PF-3845 reduces viability, migration and invasiveness of human colon adenocarcinoma Colo-205 cell line: an in vitro study[J]. Acta Biochimica Polonica, 2017, 64(3).
[5] Ihn H J, Kim Y S, Lim S, et al. PF-3845, a fatty acid amide hydrolase inhibitor, directly suppresses osteoclastogenesis through ERK and NF-κB pathways in vitro and alveolar bone loss in vivo[J]. International Journal of Molecular Sciences, 2021, 22(4): 1915.
[6] Tanaka M, Yagyu K, Sackett S, et al. Anti-inflammatory effects by pharmacological inhibition or knockdown of fatty acid amide hydrolase in BV2 microglial cells[J]. Cells, 2019, 8(5): 491.
[7] Tchantchou F, Tucker L B, Fu A H, et al. The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury[J]. Neuropharmacology, 2014, 85: 427-439.
[8] Chen H J C, Spiers J G, Sernia C, et al. Inhibition of fatty acid amide hydrolase by PF-3845 alleviates the nitrergic and proinflammatory response in rat hippocampus following acute stress[J]. International Journal of Neuropsychopharmacology, 2018, 21(8): 786-795.
PF-3845是一种双靶点抑制剂，可同时靶向脂肪酸酰胺水解酶（FAAH）和可溶性环氧化物水解酶（sEH），对FAAH和sEH的EC50值分别为0.65nM和12000nM[1]。PF-3845通过羧基化FAAH酶的丝氨酸亲核基团，实现对酶的特异性共价抑制，且在体内不与其他丝氨酸水解酶反应[2]。PF-3845可作为新型化学支架，抑制结核分枝杆菌的苯丙氨酰-tRNA合成酶[3]。
在体外，PF-3845处理48小时能显著抑制Colo-205细胞活力，IC50值为51.38μM[4]。用10μM的PF-3845处理小鼠骨髓基质细胞4天，可抑制RANKL诱导的破骨细胞分化，并显著降低细胞中树突状细胞特异性跨膜蛋白和组织蛋白酶K的mRNA表达[5]。用10μM的PF-3845预处理BV2细胞18小时，能显著抑制脂多糖诱导的前列腺素E2产生，并降低炎症基因表达[6]。
在体内，通过每日腹腔注射5mg/kg剂量的PF-3845，连续14天，可显著恢复创伤性脑损伤小鼠的海马依赖性记忆能力，并缓解小鼠焦虑症状和精细运动缺陷[7]。对大鼠单次腹腔注射5mg/kg剂量的PF-3845（60分钟），能够改善急性束缚应激引起的血浆皮质酮释放和葡萄糖动员[8]。
| Cell experiment [1]: | |
Cell lines | Colo-205 cells |
Preparation Method | Colo-205 cells were cultured in RPMI-1640 medium supplemented with 10% heat-inactivated FBS, 4mM L-glutamine, and antibiotics (50U/ml penicillin, 50μg/ml streptomycin), and 1% non-essential amino acids. Exponentially growing colorectal cancer cells were seeded at 9.3×103/well in a 96-well plate. The final concentration of DMSO in the medium did not exceed 0.02%. Cells were exposed to the PF-3845 (0.1, 1, 10, 100, and 1000μM) for 48h, then MTT reagent was added (5mg/ml PBS) and incubation was continued for 2h. MTT-formazan crystals were dissolved in 20% SDS and 50% DMF at pH 4.7, and absorbance was read at 570nm. |
Reaction Conditions | 0.1, 1, 10, 100, and 1000μM; 48h |
Applications | PF-3845 treatment inhibited the cell viability of Colo-205 cells in a dose-dependent manner. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6 mice |
Preparation Method | Twenty male C57BL/6 mice were divided into four groups: no ligation and using the vector (NL + V), no ligation and using PF-3845 (NL + PF-3845), ligation and using the vector (L + V), and ligation and using PF-3845 (L + PF-3845). The ligated group of mice had the upper second molars around the upper jaw ligated using 5-0 silk thread to induce alveolar bone destruction. The mice were intraperitoneally injected with the vector or PF-3845 (10mg/kg/day) for six days, and were sacrificed on the seventh day after which the upper jaws were collected for analysis. |
Dosage form | 10mg/kg/day for 6 days; i.p. |
Applications | PF-3845 treatment effectively inhibited the formation of osteoclasts and bone destruction and prevented the loss of alveolar bone in mice. |
References: | |
| Cas No. | 1196109-52-0 | SDF | |
| 化学名 | N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide | ||
| Canonical SMILES | C1CN(CCC1CC2=CC(=CC=C2)OC3=NC=C(C=C3)C(F)(F)F)C(=O)NC4=CN=CC=C4 | ||
| 分子式 | C24H23F3N4O2 | 分子量 | 456.46 |
| 溶解度 | DMF: 20 mg/ml,DMSO: 20 mg/ml,Ethanol: 20 mg/ml,Ethanol:PBS (pH 7.2) (1:3): 0.25 mg/ml | 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 | 2.1908 mL | 10.9539 mL | 21.9077 mL |
| 5 mM | 438.2 μL | 2.1908 mL | 4.3815 mL |
| 10 mM | 219.1 μL | 1.0954 mL | 2.1908 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
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