Brepocitinib (PF-06700841)
(Synonyms: PF-841) 目录号 : GC25168Brepocitinib (PF-06700841, PF-841) is a potent inhibitor of Tyk2 and Jak1 with IC50s of 23 nM, 17 nM, 77 nM for Tyk2, Jak1 and Jak2 respectively. It has appropriate in-family selectivity against JAK2 and JAK3.
Cas No.:1883299-62-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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- SDS (Safety Data Sheet)
- Datasheet
Brepocitinib (PF-06700841, PF-841) is a potent inhibitor of Tyk2 and Jak1 with IC50s of 23 nM, 17 nM, 77 nM for Tyk2, Jak1 and Jak2 respectively. It has appropriate in-family selectivity against JAK2 and JAK3.
The pharmacokinetics of PF-06700841 are studied in Sprague-Dawley rats following intravenous and oral administration (1 and 3 mg/kg respectively) of the tosylate salt, where the compound shows a plasma clearance of 31 mL/min/kg, a volume of distribution of 2.0 L/kg, and oral bioavailability of 83%. Following the 3 mg/kg oral dose, the Cmax is 774 ng/mL and the AUC∞ is 1340 ng.h/mL. The high oral bioavailability indicates high absorption from the gut, consistent with its in vitro passive permeability properties and high solubility[1].
[1] Fensome A, et al. J Med Chem. 2018, 61(19):8597-8612.
| Cas No. | 1883299-62-4 | SDF | Download SDF |
| 别名 | PF-841 | ||
| 分子式 | C18H21F2N7O | 分子量 | 389.4 |
| 溶解度 | DMSO: 78 mg/mL (200.31 mM);Water: Insoluble;Ethanol: 78 mg/mL (200.31 mM) | 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 | 2.5681 mL | 12.8403 mL | 25.6805 mL |
| 5 mM | 0.5136 mL | 2.5681 mL | 5.1361 mL |
| 10 mM | 0.2568 mL | 1.284 mL | 2.5681 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis
J Am Acad Dermatol 2022 Jan;86(1):148-157.PMID:34224773DOI:10.1016/j.jaad.2021.06.869.
Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and Brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.
TYK 2 inhibitors for the treatment of dermatologic conditions: the evolution of JAK inhibitors
Int J Dermatol 2022 Feb;61(2):139-147.PMID:33929045DOI:10.1111/ijd.15605.
Increasing understanding of cytokines as major drivers of immune-mediated diseases has revolutionized targeted treatments for these conditions. As the pathogenesis of autoimmune conditions is mediated by a complex interplay of various cytokines, Janus kinase (JAK) inhibitors have been of particular interest due to their ability to target multiple cytokines simultaneously. However, due to safety concerns with first generation JAK inhibitors, most notably from JAK2 and JAK3 inhibition, interest has shifted to more selective inhibition of TYK2. Three key TYK2 inhibitors that have advanced furthest in clinical trials for treatment of dermatologic autoimmune conditions are deucravacitinib (BMS-986165), Brepocitinib (PF-06700841), and PF-06826647. This review outlines the current understanding of the efficacy and safety of these three TYK2 inhibitors from completed phase I and II studies and summarizes studies currently in progress for dermatologic conditions.
A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and Brepocitinib in alopecia areata: 24-week results
J Am Acad Dermatol 2021 Aug;85(2):379-387.PMID:33757798DOI:10.1016/j.jaad.2021.03.050.
Background: Alopecia areata (AA) is an autoimmune form of hair loss with limited treatments. Objective: To evaluate the efficacy and safety of the Janus kinase inhibitors ritlecitinib and Brepocitinib in patients who have AA with ≥ 50% scalp hair loss. Methods: Patients were randomized to once-daily ritlecitinib, Brepocitinib, or placebo. The primary efficacy endpoint was a 24-week change from baseline in the Severity of Alopecia Tool (SALT) score. The key secondary efficacy endpoint was the proportion of patients achieving 30% improvement in SALT score (SALT30). Results: The ritlecitinib, Brepocitinib, and placebo groups included 48, 47, and 47 patients, respectively. At week 24, least-squares mean difference from placebo in SALT score change from baseline was 31.1 (95% confidence interval [CI], 18.8-43.5) for ritlecitinib and 49.2 (95% CI, 36.6-61.7) for Brepocitinib (P < .0001 for both comparisons with placebo). SALT30 was achieved by 50% (90% CI, 38%-62%) of patients receiving ritlecitinib, 64% (90% CI, 51%-75%) receiving Brepocitinib, and 2% (90% CI, 0%-9%) receiving placebo. Two patients experienced a serious adverse event (rhabdomyolysis) in the Brepocitinib group only. Limitations: Only a single-dosage regimen of each study drug was included. Conclusion: Treatment with ritlecitinib or Brepocitinib for 24 weeks was efficacious and generally well tolerated.
Characterizing the relationships between patient-reported outcomes and clinician assessments of alopecia areata in a phase 2a randomized trial of ritlecitinib and brepocitinib
J Eur Acad Dermatol Venereol 2022 Apr;36(4):602-609.PMID:35000236DOI:10.1111/jdv.17909.
Background: The phase 2a ALLEGRO trial (NCT02974868) investigated the safety and efficacy of ritlecitinib (PF-06651600) and Brepocitinib (PF-06700841) in adults with alopecia areata. No randomized controlled trial for alopecia areata has evaluated correlations between clinician-assessed hair loss and patient-reported outcomes. Objectives: Report scores from the Alopecia Areata Symptom Impact Scale (AASIS; a patient-reported outcome tool) and explore the relationships of those scores with clinician-assessed Severity of Alopecia Tool (SALT) scores at baseline and week 24 of the ALLEGRO trial. Methods: Adults with alopecia areata were randomized to ritlecitinib (n = 48), brepocitinib (n = 47) or placebo (n = 47). After 24 weeks, the mixed-effects model with repeated measures was used to calculate the active treatment groups' AASIS score least-squares mean differences. Relationships between AASIS and SALT scores at baseline and week 24 were evaluated by Pearson's correlation coefficients using pooled data. Results: Baseline AASIS and SALT scores were similar among treatment groups. Both active treatment groups reported significant improvements in AASIS scores at week 24 (least-squares mean differences vs. placebo for ritlecitinib, -0.8 to -2.3; brepocitinib, -0.9 to -3.7; P < 0.05 for all). At week 24, the mean SALT scores (standard deviation) improved compared with baseline [ritlecitinib, 54.4 (40.3) vs. 89.4 (15.8); brepocitinib, 31.9 (35.7) vs. 86.4 (18.1)]. The correlation coefficients between AASIS global and subscale scores and SALT scores at week 24 ranged from 0.34 to 0.58; P < 0.05 for all. Conclusions: Patients randomized to ritlecitinib or brepocitinib reported significantly improved AASIS and SALT scores at week 24 of the ALLEGRO trial compared to placebo. At week 24, medium-to-large correlations can be seen between AASIS global and subscale scores and SALT scores. Our experience with AASIS instrument highlighted several aspects that suggest new patient-reported outcome tools are needed to accurately assess patients' relevant alopecia areata related signs, symptoms and daily functioning.
Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors
Dermatol Ther (Heidelb) 2023 Feb;13(2):417-435.PMID:36592300DOI:10.1007/s13555-022-00878-9.
Plaque psoriasis is a systemic immune-mediated disease driven by interleukin-17 producing cells under the regulation of interleukin-23. Interleukin-23 signaling is mediated by the intracellular kinase tyrosine kinase 2, a Janus kinase family member. Tyrosine kinase 2 is a potential target for oral small-molecule therapies to treat psoriasis and psoriatic arthritis. A number of tyrosine kinase 2 inhibitors are in development or approved for the treatment of psoriasis or psoriatic arthritis. Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US Food and Drug Administration as a first-in-class treatment for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and is approved by Pharmaceuticals and Medical Devices Agency (PDMA) in Japan for patients with plaque psoriasis, generalized pustular psoriasis, and erythrodermic psoriasis who have had an inadequate response to conventional therapies. Deucravacitinib selectively binds to the unique tyrosine kinase 2 regulatory pseudokinase domain in an allosteric fashion, preventing a conformational change in the catalytic domain required for ATP substrate binding, thus effectively locking tyrosine kinase 2 in an inactive state. Two other tyrosine kinase 2 inhibitors in later stage clinical development, Brepocitinib (PF-06700841) and ropsacitinib (PF-06826647), are orthosteric inhibitors that target the highly conserved catalytic domain. This selective allosteric tyrosine kinase 2 inhibition may explain the improved safety profile of deucravacitinib versus orthosteric Janus kinase and tyrosine kinase 2 inhibitors. Two phase 3 psoriasis trials demonstrated deucravacitinib was efficacious and not associated with safety concerns characteristic of Janus kinase inhibitors, hence the new class designation (TYK2 inhibitor) by health authorities in the USA and Japan. Allosteric tyrosine kinase 2 inhibitors represent a promising new class of molecules for the treatment of psoriasis and psoriatic arthritis, and longer-term trials will establish their place in therapy.