JAK3 (IC50 = 145 nM)

Ritlecitinib 是一种强效的 JAK3 选择性抑制剂，抑制 JAK3 激酶活性的 IC50 为 33.1 nM，但对 JAK1、JAK2 和 TYK2 没有活性 (IC50>10,000 nM)。 Ritlecitinib 的 IC50 值分别为 244、340、407 和 266 nM，抑制 IL-2、IL-4、IL-7 和 IL-15 诱导的 STAT5 磷酸化。 Ritlecitinib 的 IC50 为 355 nM，还可以防止 IL-21 诱导的 STAT3 磷酸化。根据功能评估，Ritlecitinib 在 T 细胞分化测定中抑制 Th1 和 Th17 分化（在 Th1 环境下 5 天后通过 IFNγ 测量，在 Th17 设置下 6 天后通过 IL-17 产生测量）（IC50 值：分别为 30 nM 和 167 nM） ）。此外，ritlecitinib 可抑制 Th1 和 Th17 功能，如在 PF-06651600 治疗前已经历分化和休眠的细胞中抑制 IFNγ 产生 (IC50=48 nM) 和 IL-17 产生 (IC50=269 nM) 所证明的[1] 。

Ritlecitinib 可减少大鼠佐剂诱导的关节炎 (AIA) 模型中的爪肿胀，未结合的 EC50 为 169 nM。在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中，以 30 或 100 mg/kg 治疗性给药或以 20 或 60 mg/kg 预防性给药，可显着降低疾病的严重程度。 Ritlecitinib 在这两种啮齿动物模型中治疗炎症和自身免疫性疾病的有效性表明，仅选择性抑制 JAK3 可能足以改变人类疾病[1]。

Absorption, Distribution and Excretion
Up to 200 mg, the AUC0-tau and Cmax of ritlecitinib increase in an approximately dose-proportional manner, and steady state is reached approximately by day 4. Ritlecitinib has an absolute oral bioavailability of approximately 64%, and 1 hour after an oral dose is administered, peak plasma concentrations are achieved. Food does not have a clinically significant impact on the systemic exposures of ritlecitinib. The co-administration of a high-fat meal and a 100 mg ritlecitinib capsule reduced Cmax by 32% and increased AUCinf by 11%. Ritlecitinib was administered without regard to meals during clinical trials.
Ritlecitinib is mainly excreted through urine and feces. Approximately 66% and 20% of radiolabeled ritlecitinib are excreted in the urine and feces, respectively. Approximately 4% of the ritlecitinib dose is excreted unchanged drug in urine.
Ritlecitinib is predicted to have a volume of distribution of 1.3 L/kg.
Ritlecitinib is predicted to have a blood clearance of 5.6 mL/min/kg.

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Metabolism / Metabolites
Ritlecitinib is metabolized by cytochrome P450 (CYP) and glutathione-S-transferase (GST) enzymes. The GST enzymes participating in the metabolism of ritlecitinib include cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3, and the CYP enzymes participating in this process include CYP3A, CYP2C8, CYP1A2, and CYP2C9. No single route contributes to more than 25% of the total metabolism of ritlecitinib.

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Biological Half-Life
Ritlecitinib has a terminal half-life that ranges from 1.3 to 2.3 hours.

Hepatotoxicity
In the prelicensure clinical trials in alopecia areata, serum aminotransferase elevations occurred in 1% to 3% of ritlecitinib treated subjects, but similar rates were found in placebo recipients. The elevations were typically mild and transient, and values above 5 times the upper limit of normal (ULN) occurred in less than 1% of patients. The elevations rarely led to early discontinuations, and often resolved even without dose adjustment. In prelicensure studies in alopecia areata and other autoimmune conditions, there were no instances of liver related severe adverse events or clinically apparent liver injury attributed to ritlecitinib. Since approval and more widescale availability of ritlecitinib, there have been no published reports of hepatotoxicity associated with its use.
Finally, ritlecitinib 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 ritlecitinib has not been defined.
Likelihood score: E* (unlikely cause of idiosyncratic clinically apparent liver injury, but is a potential cause of reactivation of hepatitis B).

Hepatotoxicity
In the prelicensure clinical trials in alopecia areata, serum aminotransferase elevations occurred in 1% to 3% of ritlecitinib treated subjects, but similar rates were found in placebo recipients. The elevations were typically mild and transient, and values above 5 times the upper limit of normal (ULN) occurred in less than 1% of patients. The elevations rarely led to early discontinuations, and often resolved even without dose adjustment. In prelicensure studies in alopecia areata and other autoimmune conditions, there were no instances of liver related severe adverse events or clinically apparent liver injury attributed to ritlecitinib. Since approval and more widescale availability of ritlecitinib, there have been no published reports of hepatotoxicity associated with its use.
Finally, ritlecitinib 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 ritlecitinib has not been defined.
Likelihood score: E* (unlikely cause of idiosyncratic clinically apparent liver injury, but is a potential cause of reactivation of hepatitis B).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of ritlecitinib during breastfeeding. Because of the risk of serious adverse effects, including malignancy, the manufacturer recommends that breastfeeding be discontinued during ritlecitinib therapy and for 14 hours 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.

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Protein Binding
Ritlecitinib is 14% bound to plasma proteins.

[1]. Telliez JB, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451.
[2]. Atli Thorarensen, et al. Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyr-rolo[2,3-d]pyridinyl acrylamides. US20150158864A1.

C15H19N5O

285.158

C, 63.14; H, 6.71; N, 24.54; O, 5.61

1792180-79-0

Ritlecitinib;1792180-81-4; 2140301-97-7 (malonate) ; 2192215-81-7; 2489392-29-0

118116220

White to light yellow solid

2.1

73.9Ų

2

4

3

21

402

2

C[C@@H]1CC[C@@H](CN1C(=O)C=C)NC2=NC=NC3=C2C=CN3

CBRJPFGIXUFMTM-MNOVXSKESA-N

InChI=1S/C15H19N5O/c1-3-13(21)20-8-11(5-4-10(20)2)19-15-12-6-7-16-14(12)17-9-18-15/h3,6-7,9-11H,1,4-5,8H2,2H3,(H2,16,17,18,19)/t10-,11+/m1/s1

1-[(2R,5S)-2-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl]prop-2-en-1-one

(2R,5S)-Ritlecitinib; 1792180-79-0; ent-Ritlecitinib; CHEMBL4065559; 1-((2R,5S)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one; .

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

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

DMSO : ~220 mg/mL (~771.01 mM)

配方 1 中的溶解度: ≥ 5.5 mg/mL (19.28 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 55.0 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 5.5 mg/mL (19.28 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 55.0mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 5.5 mg/mL (19.28 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 55.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。