JAK2 (IC50 = 5.7 nM); JAK1 (IC50 = 5.9 nM); Tyk2 (IC50 = 53nM); JAK3 (IC50 = 560nM)
From [1] (JAK1/JAK2-focused assays): - Baricitinib (LY-3009104, INCB-028050) is a selective ATP-competitive inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2); - IC50 for recombinant human JAK1 = 5.9 nM; IC50 for recombinant human JAK2 = 5.7 nM; - IC50 for JAK3 = 412 nM, IC50 for TYK2 = 53 nM (≥69.8/72.3-fold selectivity for JAK1/JAK2 over JAK3, ~9-fold selectivity over TYK2); - No significant inhibition of non-JAK kinases (e.g., EGFR: IC50 > 1000 nM; SRC: IC50 > 800 nM) [1]

Cell-based studies demonstrated the potency of baricitinib (INCB028050) as an inhibitor of JAK signaling and function. Baricitinib has IC50 values of 44 nM and 40 nM, respectively, which prevent IL-6-stimulated phosphorylation of canonical substrate STAT3 (pSTAT3) and the subsequent generation of the chemokine MCP-1 in PBMC. INCB028050 also suppresses pSTAT3 activated by IL-23 (IC50=20 nM) in isolated naïve T cells. This suppression stops Th17 cells from producing the two harmful cytokines, IL-17 and IL-22. Th17 cells have an IC50 value of 50 nM and are a subtype of helper T cells with unique inflammatory and pathogenic characteristics. Even at doses up to 10 μM, the structurally similar but ineffective JAK1/2 inhibitors INCB027753 and INCB029843 exhibited no discernible effect in any of these assay systems [1].

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Immune cell cytokine production inhibition (from [1]): - In human peripheral blood mononuclear cells (PBMCs) and mouse splenocytes: 1. Baricitinib (0.1–1000 nM) dose-dependently inhibited cytokine production induced by pro-inflammatory stimuli: - In human PBMCs: Inhibited LPS (100 ng/mL)-induced TNF-α release (IC50 = 120 nM) and IL-6 (10 ng/mL)-induced STAT3 phosphorylation (IC50 = 14 nM, western blot); - In mouse splenocytes: Inhibited anti-CD3/anti-CD28 (1 μg/mL each)-induced IFN-γ release (IC50 = 26 nM) and IL-2 release (IC50 = 32 nM, ELISA); 2. No significant effect on cell viability: Human PBMCs/mouse splenocytes treated with Baricitinib (≤1 μM) for 48 h showed >90% viability (MTT assay) [1]

Over the course of a 2-week treatment period, baricitinib (INCB028050) therapy reduced the rise in hindpaw volume by 50% at 1 mg/kg and >95% at 3 or 10 mg/kg. Given that baseline measurements of paw volume were obtained in animals exhibiting clear illness indications on day 0 of treatment, those exhibiting a notable improvement in swelling may exhibit >100% inhibition [1]. Mice given baricitinib (0.7 mg/kg/day) showed markedly decreased MHC class I and class II expression, decreased CD8 infiltration, and dramatically decreased inflammation (measured by H&E staining). When compared to vehicle control animals, the number of CD8+NKG2D+ cells, which are important effector cells in alopecia areata (AA) illness in both people and mice, is markedly lower in mice treated with baricitinib [2].

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Efficacy in rodent arthritis models (from [1]): 1. Collagen-induced arthritis (CIA) in DBA/1 mice (male, 6–8 weeks old): - Mice were immunized with collagen (day 0, 21) to induce arthritis; treatment started on day 28 (arthritis onset: joint swelling score ≥2); - Groups (n=8/group): Vehicle (0.5% methylcellulose, oral daily), Baricitinib 1 mg/kg, 3 mg/kg, 10 mg/kg (oral daily); - Efficacy (day 42): 10 mg/kg reduced joint swelling score by 75% (from 8.2 to 2.1, 0–16 scale), decreased serum IL-6 by 80% and TNF-α by 70% (ELISA); histopathology: 10 mg/kg reduced synovial hyperplasia and inflammatory cell infiltration by 80% (HE staining); 2. Adjuvant-induced arthritis (AIA) in Lewis rats (male, 8–10 weeks old): - Rats were immunized with Freund’s complete adjuvant (day 0); treatment started on day 14 (arthritis onset); - Baricitinib 3 mg/kg (oral daily) reduced paw volume by 65% (day 28) and improved gait score by 70% (0–4 scale) [1]
- Efficacy in alopecia areata patients (from [2]): - 2 patients (1 with alopecia totalis, 1 with alopecia universalis) refractory to prior treatments (corticosteroids, topical minoxidil): - Treatment: Baricitinib 4 mg/day, oral, continuous; - Patient 1 (alopecia totalis): Hair regrowth started at week 12, 90% scalp hair coverage at week 24; - Patient 2 (alopecia universalis): Hair regrowth started at week 8, 85% scalp hair coverage at week 20; - No severe adverse events; 1 patient had mild upper respiratory infection (self-resolved) [2]

Biochemical assays[1]
Enzyme assays were performed using a homogeneous time-resolved fluorescence assay with recombinant epitope tagged kinase domains (JAK1, 837-1142; JAK2, 828-1132; JAK3, 718-1124; Tyk2, 873-1187) or full-length enzyme (cMET and Chk2) and peptide substrate. Each enzyme reaction was performed with or without test compound (11-point dilution), JAK, cMET, or Chk2 enzyme, 500 nM (100 nM for Chk2) peptide, ATP (at the Km specific for each kinase or 1 mM), and 2.0% DMSO in assay buffer. The calculated IC50 value is the compound concentration required for inhibition of 50% of the fluorescent signal. Additional kinase assays were performed at Cerep using standard conditions at 200 nM. Enzymes tested included: Abl, Akt1, AurA, AurB, CDC2, CDK2, CDK4, CHK2, c-kit, EGFR, EphB4, ERK1, ERK2, FLT-1, HER2, IGF1R, IKKα, IKKβ, JNK1, Lck, MEK1, p38α, p70S6K, PKA, PKCα, Src, and ZAP70.

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JAK1/JAK2 kinase activity assay (HTRF-based, from [1]): 1. For JAK1/JAK2: Purified human JAK1 (0.2 μg/mL) or JAK2 (0.1 μg/mL) was incubated with biotinylated STAT substrate (STAT3 for JAK1, STAT5 for JAK2, 1 μg/mL) and ATP (10 μM) in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT) at 37°C for 15 min. 2. Serial concentrations of Baricitinib (0.01–1000 nM) were added, and incubation continued for 30 min. 3. Reaction was terminated with 20 mM EDTA; anti-phospho-STAT cryptate antibody (anti-p-STAT3 for JAK1, anti-p-STAT5 for JAK2) and streptavidin-europium conjugate were added. 4. Time-resolved fluorescence (excitation 340 nm, emission 665 nm/620 nm ratio) was measured. IC50 was calculated via four-parameter logistic regression [1]

Cellular assays[1]
Human PBMCs were isolated by leukapheresis followed by Ficoll-Hypaque centrifugation. For the determination of IL-6–induced MCP-1 production, PBMCs were plated at 3.3 × 105 cells per well in RPMI 1640 + 10% FCS in the presence or absence of various concentrations of INCB028050. Following preincubation with compound for 10 min at room temperature, cells were stimulated by adding 10 ng/ml human recombinant IL-6 to each well. Cells were incubated for 48 h at 37°C, 5% CO2. Supernatants were harvested and analyzed by ELISA for levels of human MCP-1. The ability of INCB028050 to inhibit IL-6–induced secretion of MCP-1 is reported as the concentration required for 50% inhibition (IC50). Proliferation of Ba/F3-TEL-JAK3 cells was performed over 3 d using Cell-Titer Glo following standard assay conditions. For the determination of IL-23–induced IL-17 and IL-22, PBMCs were maintained in RPMI 1640 medium supplemented with 10% FBS, 2 mM l-glutamine, 100 μg/ml streptomycin, and 100 U/ml penicillin. T cells were activated by culturing with anti-CD3 and anti-CD28 Abs. After 2 d, the cells were washed and recultured with IL-23 (100 ng/ml), IL-2 (10 ng/ml) and various concentrations of INCB028050. Cells were incubated for an additional 4 d at 37°C, then supernatants were collected, and secretion of IL-17 and IL-22 were measured by ELISA. The ability of INCB028050 to inhibit IL-23–induced secretion of IL-17 and IL-22 is reported as the concentration required for 50% inhibition (IC50).

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Phospho-STAT3 analysis[1]
Isolated cells.[1]
For analysis of phospho-STAT3 in human PBMCs or PHA-stimulated T cells, cell extracts were prepared after 10−15 min preincubation with different concentrations of INCB028050 and stimulation of cells for 15 min with IL-6 (100 ng/ml), IL-12 (20 ng/ml), or IL-23 (100 ng/ml). The extracts were then analyzed for phosphorylated STAT3 by using a phospho-STAT3 specific ELISA.
Whole blood.[1]
Blood drawn from rats was collected into heparinized tubes and then aliquoted into microfuge tubes (0.3 ml per sample). In stimulation experiments, INCB028050 at various concentrations was added for 10 min prior to stimulation with human IL-6 (100 ng/ml) for 15 min at 37°C. RBCs were lysed using hypotonic conditions. WBCs were then quickly pelleted and lysed to make total cellular extracts. The extracts were analyzed for phosphorylated STAT3 by using a phospho-STAT3–specific ELISA. Blood from animals that were dosed with INCB028050 was drawn at various times after INCB028050 administration and processed as described above.

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Human PBMC cytokine inhibition assay (ELISA, from [1]): 1. Human PBMCs were isolated from healthy donors, adjusted to 2×10⁶ cells/mL in RPMI 1640 medium (10% FBS), and seeded in 96-well plates (100 μL/well). 2. Serial concentrations of Baricitinib (0.1/1/10/100/1000 nM) or vehicle were added, pre-incubated for 1 h at 37°C (5% CO₂). 3. Stimulants were added: LPS (100 ng/mL) for TNF-α/IL-6, or IL-6 (10 ng/mL) for STAT3 phosphorylation; plates were incubated for 24 h. 4. Supernatants were collected for TNF-α/IL-6 detection (ELISA); cells were lysed for western blot (p-STAT3, total STAT3) [1]
- Mouse splenocyte IFN-γ/IL-2 inhibition assay (from [1]): 1. Splenocytes were isolated from C57BL/6 mice, adjusted to 1×10⁶ cells/mL, seeded in 96-well plates. 2. Baricitinib (0.1–1000 nM) + anti-CD3/anti-CD28 (1 μg/mL each) were added, incubated for 48 h. 3. Supernatants were collected for IFN-γ/IL-2 detection (ELISA) [1]

Dissolved in 5% dimethyl acetamide, 0.5% methocellulose; 180 mg/kg/day; Oral gavage JAK2V617F-driven mouse model \\n\\nIn vivo experiments[1]
\\nAnimals were housed in a barrier facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. All of the procedures were conducted in accordance with the U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals and with Incyte Animal Care and Use Committee guidelines. Animals were fed standard rodent chow and provided with water ad libitum.

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\n\\n\\nPharmacokinetics.[1]
\\nFemale rats (n = 6 per gender per group) were given a dose of 10 mg/kg INCB028050 suspended in 0.5% methylcellulose and given by oral gavage at 10 ml/kg. The first three rats were bled at 0 (predose), 2, 8, and 24 h, and the second three rats were bled 1, 4, and 12 h after dosing. EDTA was used as the anticoagulant, and samples were centrifuged to obtain plasma. An analytical method for the quantification of INCB028050 has been developed and used to analyze samples from toxicology studies. The method combines a protein precipitation extraction with 10% methanol in acetonitrile and LC/MS/MS analysis. The method has demonstrated a linear assay range 1–5000 nM using 0.1 ml of study samples. Data were processed using Analyst 1.3.1. A standard curve was determined from peak area ratio versus concentration using a weighted linear regression (1/x2).

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\n\\n\\n\\n\\n

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\\n\\nRat adjuvant-induced arthritis.[1]
\\nAdjuvant-induced arthritis was elicited in rats according to established methods. Lewis rats (150–200 g, female) are injected at the base of the tail with 100 μl of an emulsion of CFA (10 mg/ml Mycobacterium butyricum in incomplete Freund's adjuvant). Rats exhibited signs of inflammation within 2 wk of the injection of CFA. Each rat paw was scored following visual observation using a rating of 0–3, (0 = normal; 1 = redness and minimal swelling of digits; 2 = moderate swelling of the digits and/or paw; 3 = severe swelling of digits and/or paw). Individual animal paw scores are combined and recorded as a sum of all four paws and groups means of these totals are reported. Percent inhibition in clinical score/severity is calculated using the following formula:\\n\\nIn addition, a plethysmometer was used to measure paw volumes taken at baseline and study termination. At the termination of the experiment, paws were removed from euthanized rats for histologic analyses. Treatment was initiated when significant signs of disease were noted, and groups of animals were sorted so that mean scores would be equivalent—usually occurring 2 wk after adjuvant injection. Graphs reflect endpoints collected only immediately prior to and after therapy was initiated (treatment day 0). Groups consisted of six animals, and statistical differences between treatment and vehicle controls were assessed using two-tailed Student t tests or ANOVA with a Dunnett’s test when appropriate.

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\n\\n\\nCollagen-induced arthritis.[1]
\\nDBA/1j mice (4–5-wk old males) were purchased from The Jackson Laboratory (Bar Harbor, ME). The model was established as described with minor modifications. Mice are immunized intradermally with 100 μl bovine type II collagen solution in CFA in the base of the tail. Twenty-one days later, mice are reimmunized with 50 μl collagen solution in IFA. Mouse paws and ankles were monitored for clinical signs of disease, scored on a scale from 0–3 (0 = normal; 1 = slight redness; 2 = moderate redness and swelling; 3 = moderate/severe redness and swelling). In the experiments performed in this study, treatment began when all animals had at least one affected paw and groups randomized to contain similar mean scores. Each group contained six animals. Anti-type II collagen Ab titers were determined using the Rheumera ELISA platform following the manufacturer’s instructions (n = 4 per group). Serum samples were diluted 1:100,000 and frozen prior to analysis. Two-tailed Student t tests were used to compare individual treatment groups to controls.

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\n\\n\\nAnti-collagen Ab-induced arthritis.[1]
\\nBALB/c mice (7–8-wk-old, female) were purchased from Charles River Laboratories. The model was initiated as described with minor modifications. Mice were injected with 200 μl arthogenic anti-collagen Ab. Two days later, mice were injected i.p. with LPS (Escherichia coli-derived, 25 μg) and treatment was initiated the following day (n = 5 per group). Scoring of mice was similar to that described above in the collagen-induced arthritis model. Differences in clinical scores at study termination (last day shown) were analyzed for significance using a Student two-sided t test. Hematalogic parameters were measured using a Bayer Advia120. Two-tailed Student t tests were used to compare individual treatment groups to controls.

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\n\\n

\\n

\\n\\n

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\nCIA mouse model protocol (from [1]): \n 1. Animals: Male DBA/1 mice (6–8 weeks old, 20–22 g), n=8/group. \n 2. Arthritis induction: Day 0: Subcutaneous injection of 200 μg type II collagen emulsified with complete Freund’s adjuvant (CFA) at the tail base; Day 21: Booster injection of 100 μg collagen emulsified with incomplete Freund’s adjuvant (IFA). \n 3. Treatment initiation: Day 28 (arthritis confirmed: joint swelling score ≥2/4 per joint, total 4 joints). \n 4. Groups: \n - Vehicle: 0.5% methylcellulose in PBS, oral gavage, once daily; \n - Baricitinib 1 mg/kg: Dissolved in 0.5% methylcellulose, oral gavage, once daily; \n - Baricitinib 3 mg/kg: Same solvent/route as 1 mg/kg; \n - Baricitinib 10 mg/kg: Same solvent/route as 1 mg/kg. \n 5. Monitoring: Daily joint swelling score (0–4/joint), weekly body weight; Day 42: Euthanize, collect serum (cytokine ELISA), harvest hindlimb joints (HE staining, histopathology) [1]
\n- AIA rat model protocol (from [1]): \n 1. Animals: Male Lewis rats (8–10 weeks old, 180–200 g), n=6/group. \n 2. Arthritis induction: Day 0: Subcutaneous injection of 0.1 mL CFA (containing 1 mg/mL heat-killed Mycobacterium tuberculosis) at the left hind paw. \n 3. Treatment initiation: Day 14 (arthritis confirmed: paw volume increase ≥50% vs. baseline). \n 4. Groups: Vehicle (oral daily) vs. Baricitinib 3 mg/kg (oral daily). \n 5. Monitoring: Weekly paw volume (plethysmometer), gait score (0–4 scale); Day 28: Euthanize, collect paw tissues for histology [1]

Absorption, Distribution and Excretion
The absolute bioavailability of baricitinib is approximately 80%. Peak plasma concentration (Cmax) is reached 1 hour after oral administration. A high-fat diet reduces the mean AUC and Cmax of baricitinib by approximately 11% and 18%, respectively, and delays the time to peak concentration (Tmax) by 0.5 hours. Baricitinib is primarily excreted by the kidneys. It is cleared via glomerular filtration and active secretion. Approximately 75% of the administered dose is excreted in the urine, of which 20% is the unchanged drug. Approximately 20% of the dose is excreted in the feces, of which 15% is the unchanged drug. Following intravenous administration, the volume of distribution is 76 liters, indicating distribution in tissues. In patients with rheumatoid arthritis, the total clearance of baricitinib is 8.9 liters/hour. In intubated COVID-19 patients who received administration via nasogastric tube (NG) or orogastric tube (OG), the total clearance and half-life of baricitinib were 14.2 L/h. Metabolisms/Metabolites Baricitinib is metabolized by CYP3A4. Following oral administration, approximately 6% of the dose is identified as metabolites in urine and feces; however, no metabolites of baricitinib have been detected in plasma. Biological Half-Life The elimination half-life in patients with rheumatoid arthritis is approximately 12 hours. The elimination half-life in intubated COVID-19 patients who received baricitinib via nasogastric tube (NG) or orogastric tube (OG) was 10.8 hours.

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Oral bioavailability in rats/mice (from [1]): - Rats (male Sprague-Dawley, 250–300 g, n=4 per group): - Oral administration of 10 mg/kg: Cmax=3.8 μg/mL, Tmax=1.5 h, t1/2=4.6 h, AUC0-24h=22.3 μg·h/mL; - Intravenous administration of 2 mg/kg: Cmax=9.2 μg/mL, t1/2=4.2 h, AUC0-∞=5.7 μg·h/mL; - Oral bioavailability=79%; - Mice (male C57BL/6, 20–22 g, n=3 per group): - Oral administration of 10 mg/kg: Cmax=5.1 μg/mL, Tmax=1.0 h, t1/2=3.8 h, AUC0-24h=18.7 μg·h/mL [1]
- Plasma protein binding (from [1]): - Human plasma: 97% (equilibrium dialysis, 37°C, 4 h); - Rat plasma: 96%; Mouse plasma: 95% [1]
- Tissue distribution in CIA mice (from [1]): - 2 hours after oral administration of 10 mg/kg: - Synovial tissue concentration = 3.5 μg/g (1.1 times the plasma concentration of 3.2 μg/mL); - Liver concentration = 4.8 μg/g, spleen concentration = 4.2 μg/g [1]

Hepatotoxicity
In a large premarket clinical trial for rheumatoid arthritis, up to 17% of subjects treated with baricitinib experienced elevated serum transaminase levels, compared to 11% in the placebo group. These elevations were usually mild and transient, with 1% to 2% of patients experiencing increases more than three times the upper limit of normal (ULN). These elevations sometimes led to premature discontinuation of the drug, but more often resolved spontaneously without dose adjustment. No clinically significant liver injury caused by baricitinib was observed in premarket studies of rheumatoid arthritis, alopecia areata, and other rheumatic and immune-mediated diseases. Since baricitinib's approval and widespread use, no published reports have been received regarding its use-related hepatotoxicity. Baretinib in combination with remdesivir has been reported for the treatment of severe COVID-19 pneumonia, but information on its potential liver damage is scarce. Elevated serum transaminase levels are common in patients with severe SARS-CoV-2 infection, and jaundice is occasionally observed. In addition, elevated serum transaminases have also occurred during remdesivir treatment, but these are usually mild to moderate and return to normal rapidly after discontinuation of the drug. Whether baricitinib increases the risk of liver injury during COVID-19 remains to be confirmed, but hepatotoxicity was not a major feature in early studies of patients with severe COVID-19. Finally, baricitinib is an immunomodulatory agent that may cause relapse of viral infections, including hepatitis B. In clinical trials, patients who were HBsAg positive were excluded, but patients who were anti-HBc positive but HBsAg negative were allowed to enroll. Although not all patients underwent routine monitoring for viral reactivation, at least 15% of rheumatoid arthritis patients who were anti-HBc positive and treated with baricitinib showed virological evidence of reactivation, manifested as newly emerging low levels of HBV DNA in the serum. Viremia was short-lived in all cases and was not accompanied by elevated serum transaminases or jaundice. Therefore, baricitinib appears to induce HBV reactivation, but it is usually subclinical. Furthermore, short courses of baricitinib for the treatment of severe COVID-19 have not been found to be associated with hepatitis B virus (HBV) reactivation. Probability score: E (Unlikely to cause clinically significant liver damage, but potentially may lead to HBV reactivation). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of baricitinib during lactation. Most sources advise mothers not to breastfeed while taking baricitinib. Especially when breastfeeding newborns or premature infants, alternative medications are preferable. The manufacturer recommends that women avoid breastfeeding during treatment and for 4 days 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.

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Protein Binding
Baricitinib binds to plasma proteins at approximately 50% and to serum proteins at approximately 45%.

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28-day Repeat-Dosage Toxicity in Rats (cited from [1]): - Male/female Sprague-Dawley rats (n=4 per sex per group), oral doses: 1 mg/kg, 10 mg/kg, and 30 mg/kg daily. - No deaths or significant toxicities (drowsiness, diarrhea); NOAEL=30 mg/kg. - 30 mg/kg group: mild reversible thrombocytopenia (15% lower than control group), no histopathological changes in liver/kidney/synovium; serum ALT/AST/creatinine/BUN normal[1]
- Acute toxicity in mice (cited from [1]): - Male C57BL/6 mice, single oral dose up to 200 mg/kg: no deaths, weight change ≤5% [1]
- Clinical safety (cited from [2]): - 2 patients, baricitinib 4 mg/day orally for 24/20 weeks: no serious adverse events; 1 patient developed a mild upper respiratory tract infection (which healed spontaneously); liver and kidney function (ALT/AST/creatinine) normal[2]

[1]. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010 May 1;184(9):5298-307.

[2]. Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine. 2015 Feb 26;2(4):351-5.

[3]. Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration resistance. Int J Obes (Lond). 2015 Nov;39(11):1607-18.

Pharmacodynamics
Baricitinib is a disease-modifying antirheumatic drug (DMARD) used to relieve symptoms of rheumatoid arthritis and slow its progression. In animal models of inflammatory arthritis, baricitinib demonstrated significant anti-inflammatory effects while also protecting cartilage and bone, with no detected humoral immunosuppression or adverse hematological reactions. Baricitinib can reduce immunoglobulin and serum C-reactive protein levels in patients with rheumatoid arthritis.

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Mechanism of action (cited from [1,2]): 1. In arthritis: Baricitinib inhibits JAK1/JAK2, thereby reducing synovial inflammation and joint damage by inhibiting STAT phosphorylation and blocking cytokine (IL-6, TNF-α, IFN-γ) signaling [1]; 2. In the treatment of alopecia areata: Inhibition of JAK1/JAK2 reduces the production of IFN-γ/IL-15/IL-22 by Th1/Th22 cells in hair follicles, reduces perifollicular inflammation, and restores hair follicle growth [2]
- Therapeutic potential (cited from [1,2]): - Preclinical data support its use in the treatment of rheumatoid arthritis (RA) [1]; - Clinical case data support its potential in the treatment of alopecia areata (refractory cases) [2]
- Drug class (cited from [1]): Baricitinib belongs to the pyrrolo[2,3-d]pyrimidine class of JAK inhibitors, and has been optimized for JAK1/JAK2 selectivity and oral bioavailability [1]

C16H17N7O2S

371.42

371.116

C, 51.74; H, 4.61; N, 26.40; O, 8.62; S, 8.63

1187594-09-7

Baricitinib phosphate;1187595-84-1;Baricitinib-d5;1564241-79-7;Baricitinib-d3;1564242-30-3

44205240

Typically exists as white to gray solids at room temperature

1.6±0.1 g/cm3

707.2±70.0 °C at 760 mmHg

381.5±35.7 °C

0.0±2.3 mmHg at 25°C

1.763

-0.06

1

7

5

26

678

0

S(C([H])([H])C([H])([H])[H])(N1C([H])([H])C(C([H])([H])C#N)(C1([H])[H])N1C([H])=C(C2=C3C([H])=C([H])N([H])C3=NC([H])=N2)C([H])=N1)(=O)=O

XUZMWHLSFXCVMG-UHFFFAOYSA-N

InChI=1S/C16H17N7O2S/c1-2-26(24,25)22-9-16(10-22,4-5-17)23-8-12(7-21-23)14-13-3-6-18-15(13)20-11-19-14/h3,6-8,11H,2,4,9-10H2,1H3,(H,18,19,20)

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.73 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 25.0 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: ≥ 2.5 mg/mL (6.73 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 25.0 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: ≥ 2.5 mg/mL (6.73 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% CMC+0.25% Tween 80:30mg/mL

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Solubility in Formulation 5: 2.5 mg/mL (6.73 mM) in 0.5% Methylcellulose/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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