Abrocitinib (PF-04965842)
(Synonyms: PF-04965842(阿布罗替尼),PF-04965842) 目录号 : GC32023
Abrocitinib (PF-04965842)是一种口服活性且选择性的Janus激酶（JAK）抑制剂，对JAK1和JAK2的IC50值分别为29nM和803nM。
Cas No.:1622902-68-4
Sample solution is provided at 25 µL, 10mM.
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Abrocitinib (PF-04965842) is a orally active and selective Janus kinase (JAK) inhibitor with IC50 values of 29nM and 803nM for JAK1 and JAK2, respectively[1]. Abrocitinib approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA)[2]. Abrocitinib also possess anti-inflammtation and can be used to treat fibrosis and traumatic brain injury[3][6].
In vitro, Abrocitinib (1µM) incubated hepatic stellate cell (HSC)-T6 for 24 hours significant decreased in the RNA levels of Col1a1, Jak1 and Acta2 and the protein levels of type I alpha 1 chain (COL1A1), JAK1, and actin alpha 2 (ACTA2). The Abrocitinib treated group also showed a significant decrease in the proportion of apoptotic cells[3]. Peripheral blood mononuclear cells were isolated and stimulated with tuberculosis (TB) antigen and Abrocitinib (0, 0.75, and 1.5µM) for 24 hours. Abrocitinib significantly reduced TB antigen-dependent T-cell activation and subsequently reduced the IFN-production[4]. Abrocitinib (0.1–1000mM) incubated with 0.3mg/mL microsomal protein HLM-103 at 37℃ revealed that the primary enzymes involved in Abrocitinib metabolism were CYP2C19, CYP2C9, CYP3A4, and CYP2B6. The enzyme kinetic parameters for the formation of major metabolites M1, M2/M3, and M4 were determined using Michaelis-Menten substrate inhibition modeling[5].
In vivo, Abrocitinib (40mg/kg of body weight, daily) orally administrated for 10 days into rat models of post-liver transplantation (LT) liver fibrosis decreased the stage of liver fibrosis and the levels of COL1A1 and ACTA2[3]. Abrocitinib (10mg/kg) administrated via the intragastric route into traumatic brain injury (TBI) mouse models could ameliorate neuroinflammation and exert a neuroprotective effect via Inhibiting the JAK1/STAT1/NF-κB Pathway. Compared to the TBI group, the Abrocitinib treatment group showed less trauma lesions, better neurological function, less blood-brain barrier (BBB) leakagea and improved intracranial blood flow[6]. Sprague-Dawley rats orally administrated Abrocitinib (20mg/kg) 30min after orally given amitriptyline (15mg/kg) and fluoxetine (5mg/kg), two commonly used antidepressants that inhibit the activities of CYP2C19 and CYP3A4. The results indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of Abrocitinib in rats. Dose adjustment of Abrocitinib may be required when it is combined with amitriptyline or fluoxetine[7].
References:
[1] Nicole Ramsey N, Wajiha Kazmi W, Matthew Phelan M,et al. JAK1 inhibition with Abrocitinib (PF-04965842) decreases allergen-specific basophil and T-cell activation in pediatric peanut allergy. J Allergy Clin Immunol Glob. 2023 Aug;2(3):100103.
[2] McLornan D P, Pope J E, Gotlib J, Harrison C N. Current and future status of JAK inhibitors. Lancet. 2021 Aug 28;398(10302):803-816.
[3] Si Z Y, Zhao S Q, Zhang Z X, et al. Bone marrow mesenchymal stem cells alleviate liver fibrosis after rat liver transplantation through JAK1/STAT5 pathway. Stem Cell Res Ther. 2025 May 1;16(1):217.
[4] Li Y T, Tan X, Nie S, et al. Abrocitinib interferes with the performance of T-SPOT.TB assay for latent tuberculosis reactivation: An in vitro study. J Am Acad Dermatol. 2025 May;92(5):1124-1125.
[5]Bauman J N, Doran A C, Ahmad A K, et al. The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans. Drug Metab Dispos. 2022 Aug;50(8):1106-1118.
[6] Li T, Li L, Peng R L, et al. Abrocitinib (PF-04965842) Attenuates Microglia-Mediated Neuroinflammation after Traumatic Brain Injury via Inhibiting the JAK1/STAT1/NF-κB Pathway. Cells. 2022 Nov 13;11(22):3588.
[7] Chen L G, Chen X H, Liu J P, et al. Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats. Chem Biol Interact. 2024 Jul 1:397:111041.
Abrocitinib (PF-04965842)是一种口服活性且选择性的Janus激酶（JAK）抑制剂，对JAK1和JAK2的IC50值分别为29nM和803nM[1]。Abrocitinib已获美国食品药品监督管理局（FDA）批准用于治疗特应性皮炎（AD）[2]，还具有抗炎作用，可用于治疗纤维化和创伤性脑损伤[3][6]。
体外实验中，Abrocitinib（1µM）与肝星状细胞HSC-T6共孵育24小时，可显著降低Col1a1、Jak1和Acta2的RNA水平以及Ⅰ型胶原α1链（COL1A1）、JAK1和α-平滑肌肌动蛋白（ACTA2）的蛋白水平，Abrocitinib处理组细胞凋亡比例也显著降低[3]。将外周血单个核细胞分离并用结核（TB）抗原刺激，再与Abrociticinib（0、0.75、1.5µM）共孵育24小时，Abrocitinib可显著减少TB抗原依赖的T细胞激活，进而减少干扰素产生[4]。Abrocitinib（0.1-1000mM）与0.3mg/mL微粒体蛋白HLM-103在37℃共孵育，发现参与Abrocitinib代谢的主要酶为CYP2C19、CYP2C9、CYP3A4和CYP2B6，采用米氏-门特恩底物抑制模型确定了主要代谢产物M1、M2/M3和M4的酶动力学参数[5]。
体内实验中，Abrocitinib（40mg/kg体重，每日一次）口服给药10天，用于肝移植（LT）后肝纤维化大鼠模型，可降低肝纤维化程度以及COL1A1和ACTA2水平[3]。Abrocitinib（10mg/kg）通过灌胃给药，用于创伤性脑损伤（TBI）小鼠模型，可通过抑制JAK1/STAT1/NF-κB通路减轻神经炎症并发挥神经保护作用，与TBI组相比，Abrocitinib治疗组创伤性病变更少，神经功能更好，血脑屏障（BBB）渗漏更少，脑内血流改善[6]。Sprague-Dawley大鼠在口服给予阿米替林（15mg/kg）和氟西汀（5mg/kg）两种常用的抑制CYP2C19和CYP3A4活性的抗抑郁药后30分钟，经口给予Abrocitinib（20mg/kg）。结果表明，阿米替林和氟西汀能显著增加大鼠血浆中Abrocitinib的浓度。当Abrocitinib与阿米替林或氟西汀联合使用时，可能需要调整剂量[7]。
| Kinase experiment [1]: | |
Preparation Method | Abrocitinib (0.1–1000mM) was incubated in 100mM potassium phosphate buffer (pH 7.4) containing 3mM MgCl2 and 0.3mg/mL microsomal protein HLM-103 at 37℃. Reactions were initiated with NADPH (1.2mM) immediately followed by substrate and terminated after 15 minutes by quenching aliquots of the incubation mixture with acetonitrile-containing internal standard (10ng/mL). Samples were centrifuged (1700g) for 10 minutes, and 100mL of supernatant was transferred to a 96 deep-well plate. The supernatants were dried down under a stream of nitrogen and reconstituted in 100mL of 90% water/10% acetonitrile. Incubations for enzyme kinetic determination were conducted in triplicate. |
Reaction Conditions | 0.1–1000mM; 15min |
Applications | The metabolism of Abrocitinib in human liver microsomes mainly occurs through CYP2C19, CYP2C9, CYP3A4 and CYP2B6. Enzyme kinetic parameters and intrinsic clearance values for the formation of Metabolite 1, Metabolite2/Metabolite3, and Metabolite 4 from Abrocitinib metabolism in human liver microsomes were determined (e.g. for Metabolite 1, Km, Michaelis constant = 143 ± 20mM; Vmax, maximum rate of metabolism=26.7 ± 2.2pmol/min per mg). |
| Cell experiment [2]: | |
Cell lines | Mouse BV2 microglial cells |
Preparation Method | Mouse BV2 microglial cells were exposed to LPS to mimic cerebral neuroinflammation after traumatic brain injury (TBI) in vitro. To evaluate its effects on microglial polarization, Abrocitinib (100nM, 500nM, or 1µM) was added to the culture medium for the management of LPS (10µg/mL). The treated BV2 cells were collected after 6h of LPS irritation for further immunofluorescence (IF) staining. |
Reaction Conditions | 100nM, 500nM, or 1µM; 6h |
Applications | Abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that Abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. |
| Animal experiment [3]: | |
Animal models | Sprague–Dawley (SD) rats |
Preparation Method | The animals were randomly divided into the Sham group, liver transplantation (LT) group, LT+BMSC group, LT+Abrocitinib group, with 6 animals in each group. The LT group was subjected to a transplantation of the liver with a cold storage time of 4h. The LT+BMSC group received 5×106 BMSCs by injection through the portal vein after blood flow opening during LT. In addition to LT, the LT+Abrocitinib group received Abrocitinib (40mg/kg of body weight, per os, daily) for 10 days. |
Dosage form | 40mg/kg; per os; daily for 10 days |
Applications | LT+Abrocitinib group showed reduced hepatic lobular structural disorder, fibrous connective tissue proliferation, and inflammatory cell infiltration in the HE staining camparing to LT group. LT+Abrocitinib group also showed a significant decrease in the RNA levels of Col1a1, Jak1, Acta2, and Casp3. The protein levels of COL1A1, JAK1, ACTA2, and CASP3 were significantly reduced in the LT+Abrocitinib group. |
References: | |
| Cas No. | 1622902-68-4 | SDF | |
| 别名 | PF-04965842(阿布罗替尼),PF-04965842 | ||
| Canonical SMILES | CN([C@H]1C[C@@H](NS(CCC)(=O)=O)C1)C2=C3C(NC=C3)=NC=N2 | ||
| 分子式 | C14H21N5O2S | 分子量 | 323.41 |
| 溶解度 | DMSO : 125 mg/mL (386.51 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0921 mL | 15.4603 mL | 30.9205 mL |
| 5 mM | 0.6184 mL | 3.0921 mL | 6.1841 mL |
| 10 mM | 0.3092 mL | 1.546 mL | 3.0921 mL |
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