JAK1/2

In an in vitro kinase activity assay, deuruxolitinib had greater inhibitory potency for JAK1, JAK2 and TYK2 relative to JAK3. The relevance of inhibition of JAK enzymes to therapeutic effectiveness is not currently known. Deuruxolitinib inhibited whole blood IL-6 stimulated pSTAT3 in healthy subjects 2 hours postdose. The relevance of this finding in patients is unknown.
The Janus kinase‒signal transducer and activator of transcription (JAK-STAT) pathway, which involves four JAK kinases - JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2) - is activated by various cytokine receptors and regulate the expression of mediators responsible for hematopoiesis and immune function, such as type I and type II cytokines and growth factors. JAK signalling involves the recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus, leading to modulation of gene expression. Dysregulated JAK activity, leading to aberrant immune responses, has been characterized in various inflammatory conditions, including alopecia areata. For example, high levels of IFN-γ and CD8+NKG2D+T cells, which are activated by JAK signalling, are believed to cause autoantigen expression and an autoimmune attack on hair follicles. Deuruxolitinib is a Janus kinase (JAK) inhibitor that aims to attenuate the inflammatory response around hair follicles. It selectively targets JAK1 and JAK2.

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Drug compounds have included stable heavy isotopes of elements like carbon and hydrogen, mostly as tracers that affect quantification during drug development. It's possible that the pharmacokinetics and effects of medications cause mutagenesis to be a worry. [2]. Possible benefits of compounds with delayed generation: (1) The pharmacokinetic properties of the molecule, or the possible benefits of delayed generation compounds, may be prolonged by these substances. This may enhance the compound's tolerance, efficacy, and safety. (2) Boost intestinal absorption. Deuterated chemicals have the potential to decrease the level of first-pass renal function that is required in the intestinal wall and colon, hence increasing the amount of non-renal function medications that are able to reach their intended site of action. The ability to be bioavailable incredibly strong, active at low concentrations, and more tolerable. (3) Enhance the properties of metabolism. The production process may lessen toxicity or reactivity, leading to better medications. (4) Boost the security of medications. Deuterated substances Alternatively, they are harmless and can lessen or eliminate the negative effects of medication components. (5) Preserve medicinal qualities. According to earlier research, deuterated molecules should maintain biological efficacy and selectivity comparable to hydrogen analogs.

Deuruxolitinib is an orally available small molecule inhibitor of Janus kinases that is used to treat severe alopecia areata. Deuruxolitinib is associated with a low rate of transient and usually mild elevations in serum aminotransferase levels during therapy but has not been linked to cases of clinically apparent acute liver injury.
DEURUXOLITINIB is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 3 investigational indications.

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Background: Alopecia areata (AA) is a hair loss disorder that can seriously impact quality of life. Janus kinase (JAK) inhibitors, including deuruxolitinib, have previously demonstrated significant hair regrowth in AA.
Objective: The Phase 3 THRIVE-AA1 randomized, double-blinded, placebo-controlled trial (NCT04518995) evaluated the safety and efficacy of the oral JAK1/JAK2 inhibitor deuruxolitinib in adult patients with AA.
Methods: Patients aged 18-65 years with ≥50% hair loss were randomized to deuruxolitinib 8 mg twice daily, deuruxolitinib 12 mg twice daily, or placebo for 24 weeks. The primary end point was the percentage of patients achieving a Severity of Alopecia Tool score ≤20. A key secondary end point was the percentage of satisfaction of hair patient-reported outcome responders.
Results: Significantly higher proportions of patients taking deuruxolitinib met the primary end point (8 mg 29.6%; 12 mg 41.5% versus placebo 0.8%). Both deuruxolitinib doses achieved significant improvements in all secondary end points versus placebo, including satisfaction of hair patient-reported outcome (8 mg 42.1%; 12 mg 53.0% versus placebo 4.7%). Most treatment-emergent adverse events were mild or moderate, consistent with other oral JAK inhibitors.
Limitations: Further studies are required to understand longer-term safety, efficacy, and impact of treatment cessation.
Conclusion: Both doses of deuruxolitinib were effective for hair regrowth. Patient satisfaction aligned with hair growth.[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
In healthy subjects, after oral administration of derusoxutinib, Cmax and AUC increased proportionally over a dose range of 8 mg to 48 mg (equivalent to 6 times the approved recommended dose). Following twice-daily dosing, steady-state plasma drug concentrations were reached within 1 to 2 days with minimal accumulation. The bioavailability of derusoxutinib is 90%, with peak plasma concentrations reached within 1.5 hours. No clinically significant differences in the pharmacokinetics of derusoxutinib were observed after ingestion of a high-fat, high-calorie meal (approximately 50% fat, 800–1000 calories).
Elimination Route
No detectable amount of parent drug was found in urine or feces following a single dose of radiolabeled derusoxutinib.
Volume of Distribution
The steady-state volume of distribution is approximately 50 liters.
Protein Binding
The plasma protein binding rate of derusoxutinib is 91.5%, with a plasma concentration-to-plasma ratio of approximately 1.3.
Metabolism/Metabolites
Derusoxutinib is primarily metabolized via CYP2C9 (76%) and CYP3A4 (21%), with a small amount metabolized via CYP1A2 (3%). The two most abundant metabolites are C-21714 and C-21717, each accounting for approximately 5% of the total drug-related AUC, and their pharmacological activity is approximately 10 times lower than that of derusoxutinib. The exact metabolic pathway of derusoxutinib and the structures of its metabolites have not been fully elucidated.
Biological Half-Life
The mean elimination half-life is approximately 4 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the clinical use of Deuruxolitinib during lactation. Because Deuruxolitinib binds to plasma proteins at a rate of 91.5%, its concentration in breast milk may be very low. The manufacturer recommends discontinuing breastfeeding during Deuruxolitinib treatment and for one week after the last dose.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.
Hepatotoxicity
In premarketing clinical trials for alopecia areata, the incidence of elevated serum transaminases was less than 1% in subjects treated with Deuruxolitinib, and no symptomatic or jaundice-related elevations of ALT or AST occurred. These elevations were generally mild and transient and did not warrant dose adjustment or discontinuation. No serious liver-related adverse events or drug-induced liver injury were reported in premarketing studies of Deuruxolitinib. Since its approval, no published reports of hepatotoxicity associated with its use have been received, but clinical experience with its use is limited. Finally, Deuruxolitinib is an immunomodulatory agent and may cause relapse of viral infections, including hepatitis B. Other JAK inhibitors have also been reported to be associated with rare cases of hepatitis B relapse, but these cases are usually asymptomatic and self-limiting. The risk of hepatitis B virus reactivation is not clear in HBsAg-positive or anti-HBc-positive but HBsAg-negative patients treated with Deuruxolitinib, as these patients with positive viral markers were excluded from pre-registration trials. Probability score: E (Unlikely a cause of clinically significant liver injury, but a potential cause of hepatitis B virus reactivation). The incidence of adverse events with Deuruxolitinib was similar across groups, and overall tolerability was good. In both Deuruxolitinib treatment groups, ≥5% of patients experienced headache, acne, and elevated serum creatine phosphokinase, while serious adverse events were uncommon (the investigators considered only 2 cases potentially related to the study drug). Treatment discontinuation due to adverse events was rare, 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 derivative of ruxotinib that selectively inhibits Janus kinases (JAK) JAK1 and JAK2. Deuteration allows the drug to avoid extensive oxidative metabolism around the cyclopentyl ring, thereby prolonging the duration of Deuruxolitinib's pharmacological activity. On July 26, 2024, Deuruxolitinib received FDA approval for the treatment of severe alopecia areata. Alopecia areata is an autoimmune disease that attacks hair follicles, leading to unpredictable hair loss on the scalp and other parts of the body. The Janus kinase (JAK) signaling and activating transcription factor (STAT) pathway is closely related to the pathophysiology of alopecia areata because it regulates the expression of inflammatory mediators. Deuruxolitinib's mechanism of action is to block the inflammatory response induced by JAK. Deuruxolitinib is a Janus kinase inhibitor. The mechanisms of action of derusotinib include: Janus kinase inhibitor, breast cancer resistance protein inhibitor, bile acid export pump inhibitor, organic anion transporter 3 inhibitor, and multidrug and toxin efflux transporter 2K 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

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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