JAK3 (IC50 = 145 nM)

Ritlecitinib is a powerful JAK3-selective inhibitor that has an IC50 of 33.1 nM for inhibiting JAK3 kinase activity, but no activity (IC50>10,000 nM) against JAK1, JAK2, and TYK2. With IC50 values of 244, 340, 407, and 266 nM, respectively, ritlecitinib suppresses the phosphorylation of STAT5 induced by IL-2, IL-4, IL-7, and IL-15. With an IC50 of 355 nM, ritlecitinib also prevents IL-21-induced STAT3 phosphorylation. Ritlecitinib inhibits Th1 and Th17 differentiation (measured by IFNγ after 5 days under Th1 circumstances and IL-17 production after 6 days under Th17 settings) in T-cell differentiation assays, according to functional assessment (IC50 values: 30 nM and 167 nM, respectively). Additionally, ritlecitinib inhibits Th1 and Th17 function as demonstrated by the suppression of IFNγ production (IC50=48 nM) and IL-17 production (IC50=269 nM) in cells that have undergone prior differentiation and resting before PF-06651600 treatment[1].

Ritlecitinib reduces paw swelling in the rat adjuvant-induced arthritis (AIA) model, with an unbound EC50 of 169 nM. In the experimental autoimmune encephalomyelitis (EAE) mouse model, ritlecitinib, administered either therapeutically at 30 or 100 mg/kg or prophylactically at 20 or 60 mg/kg, significantly reduces the severity of the disease. Ritlecitinib's effectiveness in treating inflammatory and autoimmune diseases in these two rodent models shows that JAK3-selective inhibition alone may be enough to modify disease in humans[1].

Absorption, Distribution and Excretion
The AUC0-τ and Cmax of litertinib increase approximately dose-proportionately at doses up to 200 mg, reaching steady state around day 4. The absolute oral bioavailability of litertinib is approximately 64%, with peak plasma concentrations reached 1 hour after oral administration. Food has no clinically significant effect on systemic exposure to litertinib. Concomitant administration of a high-fat meal and 100 mg litertinib capsules decreased Cmax by 32% and increased AUCinf by 11%. During clinical trials, litertinib administration was not affected by food intake. Litertinib is primarily excreted via urine and feces. Approximately 66% and 20% of radiolabeled litertinib are excreted in urine and feces, respectively. Approximately 4% of the litertinib dose is excreted unchanged in the urine. The expected volume of distribution for litertinib is 1.3 L/kg.
The expected plasma clearance of litexitinib is 5.6 mL/min/kg.
Metabolism/Metabolites

Litexitinib is metabolized via cytochrome P450 (CYP) and glutathione S-transferase (GST). GST enzymes involved in litexitinib metabolism include cytoplasmic GST A1/3, M1/3/5, P1, S1, T2, Z1, and microsomal GST 1/2/3. CYP enzymes involved in this process include CYP3A, CYP2C8, CYP1A2, and CYP2C9. No single pathway contributes more than 25% to the total metabolism of litexitinib.
Biological Half-Life

The terminal half-life of litexitinib is 1.3 to 2.3 hours.

Hepatotoxicity
In premarketing clinical trials of alopecia areata, 1% to 3% of subjects treated with litercitinib experienced elevated serum transaminases, with a similar incidence observed in the placebo group. These elevations were usually mild and transient, exceeding 5 times the upper limit of normal in less than 1% of patients. These elevations rarely led to early discontinuation of the drug and usually resolved spontaneously without dose adjustment. In premarketing studies of alopecia areata and other autoimmune diseases, no serious adverse liver events or clinically significant liver injury associated with litercitinib were observed. Since the approval and widespread use of litercitinib, no reports of hepatotoxicity related to its use have been published. Finally, litercitinib is an immunomodulatory agent and may cause relapse of viral infections, including hepatitis B. Other JAK inhibitors have also been associated with rare cases of hepatitis B relapse, but these cases are usually asymptomatic and self-limiting. The risk of hepatitis B relapse in patients treated with litercitinib who are HBsAg positive or anti-HBc positive but HBsAg negative has not been established.
Probability Score: E (Unlikely to cause clinically significant liver injury, but may be a potential cause of hepatitis B relapse).
Hepatotoxicity
In premarketing clinical trials of litecitinib, elevated serum transaminases occurred in 1% to 3% of subjects in the litecitinib treatment group, with a similar incidence observed in the placebo group. These elevations were generally mild and transient, with less than 1% of patients exceeding 5 times the upper limit of normal (ULN). These elevations rarely led to early discontinuation of the drug and usually resolved spontaneously without dose adjustment. In premarketing studies of alopecia areata and other autoimmune diseases, no serious adverse liver events or clinically significant liver injury associated with litecitinib were identified. Since the approval and widespread use of litecitinib, there have been no published reports of hepatotoxicity related to its use.
Finally, litecitinib is an immunomodulatory agent and may cause relapse of viral infections, including hepatitis B. Other JAK inhibitors have also been associated with rare cases of hepatitis B relapse, but these cases are usually asymptomatic and self-limiting. The risk of hepatitis B virus reactivation in HBsAg-positive or anti-HBc-positive but HBsAg-negative patients receiving litecitinib is not well understood. Probability score: E (Unlikely to cause liver injury with specific clinical manifestations, but may be a potential cause of hepatitis B virus reactivation). Pregnancy and Lactation Use ◉ Overview of Lactation Use There is currently no information regarding the clinical use of litecitinib during lactation. Due to the risk of serious adverse reactions, including malignancy, the manufacturer recommends discontinuing breastfeeding during litecitinib treatment and within 14 hours of the last dose. ◉ Effects on Breastfed Infants No published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information was found as of the revision date. Protein Binding Litecitinib binds to plasma proteins at a rate of 14%.

[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

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

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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)

Solubility in Formulation 1: ≥ 5.5 mg/mL (19.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5.5 mg/mL (19.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 5.5 mg/mL (19.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)