JAK1/2

在体外激酶活性检测中，与JAK3相比，deuruxolitinib对JAK1、JAK2和TYK2具有更强的抑制效力。目前尚不明确抑制JAK酶与临床疗效之间的相关性。在健康受试者中，deuruxolitinib在给药2小时后抑制了全血IL-6刺激的pSTAT3。该发现在患者中的相关性尚不清楚。 Janus激酶-信号转导与转录激活因子（JAK-STAT）通路涉及四种JAK激酶（JAK1、JAK2、JAK3和酪氨酸激酶2）。该通路被多种细胞因子受体激活，并调控与造血和免疫功能相关的介质（如I型和II型细胞因子及生长因子）的表达。JAK信号转导包括将STATs（信号转导与转录激活因子）募集至细胞因子受体、激活STATs以及随后STATs定位于细胞核，从而调控基因表达。JAK活性失调导致异常的免疫反应，这已被认为是多种炎症性疾病（包括斑秃）的特征。例如，由JAK信号激活的高水平IFN-γ和CD8+NKG2D+T细胞被认为会引起自身抗原表达，并对毛囊产生自身免疫攻击。Deuruxolitinib是一种Janus激酶（JAK）抑制剂，旨在减轻毛囊周围的炎症反应。它选择性地靶向JAK1和JAK2。

---

药物化合物包含碳和氢等元素的稳定重同位素，主要作为影响药物开发过程中定量的示踪剂。药物的药代动力学和作用可能会引起突变，令人担忧。[2]。具有以下性质的化合物的可能好处延迟生成：
(1) 这些物质可能会延长分子的药代动力学特性或延迟生成化合物的可能益处。这可能会增强化合物的耐受性、功效和安全性。
(2) 促进肠道吸收。氘代化学物质有可能降低肠壁和结肠所需的首过肾功能水平，从而增加能够到达其预期作用部位的非肾功能药物的数量。
(3）增强代谢特性，生产过程中可以降低毒性或反应性，从而产生更好的药物。
(4）提高药品安全性。另外，氘代物质是无害的，可以减轻或消除药物成分的负面影响。
(5) 保存药用品质。根据早期的研究，氘代分子应该保持与氢类似物相当的生物功效和选择性。

Deuruxolitinib是一种口服有效的Janus激酶小分子抑制剂，用于治疗重度斑秃。治疗期间，deuruxolitinib与一过性且通常为轻度的血清转氨酶水平升高相关，发生率较低，且尚未有报道表明其与临床上明显的急性肝损伤病例相关。
DEURUXOLITINIB是一种小分子药物，其最高临床试验阶段为III期（针对所有适应症），并有3个在研适应症。

---

背景：斑秃（AA）是一种可严重影响生活质量的脱发疾病。包括deuruxolitinib在内的Janus激酶（JAK）抑制剂此前已被证明可在AA中实现显著的毛发再生。 目的：3期THRIVE-AA1随机、双盲、安慰剂对照试验（NCT04518995）评估了口服JAK1/JAK2抑制剂deuruxolitinib在成人AA患者中的安全性和有效性。 方法：年龄18-65岁、毛发脱落≥50%的患者被随机分配接受deuruxolitinib 8 mg每日两次、deuruxolitinib 12 mg每日两次或安慰剂治疗24周。主要终点是达到斑秃严重程度工具评分≤20的患者百分比。一个关键的次要终点是患者报告结果（毛发满意度）的应答者百分比。 结果：服用deuruxolitinib的患者中，达到主要终点的比例显著更高（8 mg组29.6%；12 mg组41.5%，对比安慰剂组0.8%）。与安慰剂相比，两种deuruxolitinib剂量在所有次要终点上均实现了显著改善，包括患者报告的毛发满意度（8 mg组42.1%；12 mg组53.0%，对比安慰剂组4.7%）。大多数治疗中出现的不良事件为轻度或中度，这与其他口服JAK抑制剂的情况一致。 局限性：需要进一步研究以了解更长期的安全性、有效性以及停止治疗的影响。 结论：两种剂量的deuruxolitinib对毛发再生均有效。患者满意度与毛发生长情况一致。[3]

Study procedures [3]
Patients were randomized in a 3:5:2 ratio to receive oral deuruxolitinib 12 mg twice daily, deuruxolitinib 8 mg twice daily, or placebo. Randomization was stratified by baseline scalp hair loss (partial [SALT 50-94] or complete/near-complete [SALT ≥95]) and performed using an interactive web-response system. Identical tablets and packaging were used for deuruxolitinib and placebo to maintain investigator and patient/caregiver blinding throughout the study. Individualized dose adjustment was not permitted during the treatment period.

Absorption
Following oral administration of deuruxolitinib, Cmax and AUCs increased dose-proportionally over a dose range from 8 mg to 48 mg (6 times the approved recommended dosage) in healthy subjects. Steady-state plasma concentrations were achieved within one to two days, with minimal accumulation, after twice daily administration. Deuruxolitinib bioavailability is 90%, with peak plasma concentrations reached within 1.5 hours. No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed following the administration of a high-fat, high-calorie meal (approximately 50% fat and 800-1000 calories).

Route of Elimination
After a single dose of radiolabeled deuruxolitinib, there was no unchanged dose recovered in either urine or feces.

Volume of Distribution
The steady-state volume of distribution is approximately 50 L.

Protein Binding
Deuruxolitinib plasma protein binding is 91.5% and blood to plasma concentration ratio is approximately 1.3.

Metabolism / Metabolites
Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%) and to a lesser extent by CYP1A2 (3%). The two most abundant human metabolites C-21714 and C-21717, each of which accounted for approximately 5% of total drug-related AUC and both are approximately 10-fold less pharmacologically active than deuruxolitinib. The exact metabolic pathways of deuruxolitinib and the structures of its metabolites have not been fully characterized.

Biological Half-Life
The mean elimination half-life is approximately four hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of deuruxolitinib during breastfeeding. Because deuruxolitinib is 91.5% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during deuruxolitinib therapy and for 1 week after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

Hepatotoxicity
In the prelicensure clinical trials in alopecia areata, serum aminotransferase elevations occurred in less than 1% of deuruxolitinib-treated subjects and there were no instances of ALT or AST elevations accompanied by symptoms or jaundice. The elevations were typically mild and transient and did not lead to dose adjustments or discontinuations. In prelicensure studies in alopecia areata, there were no instances of liver related severe adverse events or drug induced liver injury. Since approval of deuruxolitinib, there have been no published reports of hepatotoxicity associated with its use, but clinical experience with it has been limited.
Finally, deuruxolitinib is an immune modulatory agent and has the potential of causing reactivation of viral infections including hepatitis B. Other JAK inhibitors have been implicated in rare instances of reactivation of hepatitis B, although the episodes were usually asymptomatic and self-limited in course. The risk of reactivation of hepatitis B in patients with HBsAg or with anti-HBc without HBsAg who are treated with deuruxolitinib has not been defined as patients with these viral markers were excluded from the preregistration trials.
Likelihood score: E* (unlikely cause of idiosyncratic clinically apparent liver injury but is a potential cause of reactivation of hepatitis B).

---

Deuruxolitinib had a similar incidence of AEs across groups and was generally well tolerated. Headache, acne, and increased blood creatine phosphokinase occurred in ≥5% of patients in both deuruxolitinib groups, while serious AEs were uncommon (and only 2 were considered by the study investigator to be potentially related to the study drug). Few treatment discontinuations occurred due to AEs, and no myocardial infarction, stroke, or thromboembolic events occurred. Herpes zoster was rare.[3]

[1]. Treatment of hair loss disorders with deuterated jak inhibitors. Patent WO2017192905A1.

[2]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019 Feb;53(2):211-216.

[3]. Efficacy and safety of deuruxolitinib, an oral selective Janus kinase inhibitor, in adults with alopecia areata: Results from the Phase 3 randomized, controlled trial (THRIVE-AA1). J Am Acad Dermatol. 2024 Nov;91(5):880-888.

Deuruxolitinib is a deuterated form of [ruxolitinib] that selectively inhibits Janus kinases (JAK) JAK1 and JAK2. Deuteration allows the drug to circumvent extensive oxidative metabolism around the cyclopentyl ring, which increases the duration of the pharmacological activity of deuruxolitinib. On July 26, 2024, deuruxolitinib was approved by the FDA for the treatment of severe alopecia areata. Alopecia areata is an autoimmune condition that attacks the hair follicles and leads to unpredictable hair loss in the scalp and other areas of the body. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway has been implicated in the pathophysiology of alopecia areata, as it regulates the expression of inflammatory mediators. Deuruxolitinib works to block the inflammatory responses caused by JAKs.
Deuruxolitinib is a Janus Kinase Inhibitor. The mechanism of action of deuruxolitinib is as a Janus Kinase Inhibitor, and Breast Cancer Resistance Protein Inhibitor, and Bile Salt Export Pump Inhibitor, and Organic Anion Transporter 3 Inhibitor, and Multidrug and Toxin Extrusion Transporter 2 K Inhibitor.

C17H18N6

314.414315700531

314.209

C, 64.94; H, 8.33; N, 26.73

1513883-39-0

Ruxolitinib;941678-49-5;(Rac)-Ruxolitinib-d9;2469553-67-9; 1513883-39-0; 2147706-60-1 (phosphate)

72704611

Typically exists as white to off-white solids at room temperature

2.1

83.2Ų

1

4

4

23

453

1

[2H]C1(C(C(C(C1([2H])[2H])([2H])[2H])([2H])[2H])[C@@H](CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3)[2H]

HFNKQEVNSGCOJV-FBXGHSCESA-N

InChI=1S/C17H18N6/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16/h6,8-12,15H,1-5H2,(H,19,20,21)/t15-/m1/s1/i1D2,2D2,3D2,4D2

(3R)-3-(2,2,3,3,4,4,5,5-octadeuteriocyclopentyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile

Deuruxolitinib; D8-ruxolitinib; CTP-543; Deuruxolitinib [USAN]; 1513883-39-0; 0CA0VSF91Y; UNII-0CA0VSF91Y;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

---

注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

View More

注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

---

口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

View More

口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

---

注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。