HSC proliferation was inhibited by ivarmacitinib (SHR0302; 1 nM-10 µM; 48 hours; HSC) therapy in a concentration-dependent manner [2]. Ivarmacitinib (1 nM–10 µM) inhibits the migration, proliferation, and activation of HSCs [2]. HSC apoptosis is induced by ivarmacitinib (1 nM–10 µM; 48 hours; HSC) therapy [2]. Ivarmacitinib (1 nM-10 µM; 48 hours; HSC) therapy markedly lowered Bcl-2 expression and enhanced caspase-3 and Bax activation. Moreover, SHR0302 prevents the Akt signaling pathway from being activated [2]. Identification of cell proliferation [2]

Ivarmacitinib (SHR0302; 0.3-3.0 mg/kg; intragastric; twice daily; for 14 days; male Sprague-Dawley (SD) rats) treatment alleviated histopathological changes in the spleen and joints of AA rats and inhibited arthritis by reducing the arthritis index, global arthritis assessment, and paw swelling severity of AA rats [1]. Ivatinib has the ability to impede the growth of T, B, and fibroblast-like synoviocytes (FLS), reduce the levels of cytokines TNF-α, IL-1β, and IL-17, as well as antibodies IgG1 and IgG2a. Additionally, it can block the ratio of Th17 to total B and phosphorylate JAK1-STAT3[1].

Cell proliferation detection [2]
Cell Types: Hepatic stellate cells (HSC)
Tested Concentrations: 1 nM, 10 nM, 100 nM, 1 μM, 10 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Inhibitory effect on HSC proliferation, and the inhibitory effect is measured by concentration Dependency occurs.

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Apoptosis analysis [2]
Cell Types: Hepatic stellate cells (HSC)
Tested Concentrations: 1 nM, 10 nM, 100 nM, 1 μM, 10 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Induced HSC apoptosis.

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Western Blot Analysis[2]
Cell Types: Hepatic stellate cells (HSC)
Tested Concentrations: 1 nM, 10 nM, 100 nM, 1 μM, 10 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Dramatically increased activation of caspase-3 and Bax in HSCs , and reduce the expression of Bcl-2. Also inhibits the activation of the Akt signaling pathway.

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats (150-180 g) injected with complete Freund's adjuvant (CFA) [1]
Doses: 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg
Route of Administration: Administered by gavage; twice (two times) daily; for 14 days
Experimental Results: Suppressed the severity of adjuvant-induced arthritis (AA) in rats and diminished the severity of adjuvant-induced arthritis (AA) in AA rats by reducing arthritis index, global arthritis assessment, and foot swelling Histopathology of the spleen and joints.

Absorption, Distribution and Excretion
Following oral administration, the median time to peak concentration of imatinib is approximately 1 hour. Biological Half-Life Following oral administration, the half-life of imatinib ranges from 8.33 to 9.87 hours, increasing slightly with increasing dose.

[1]. JAK1-STAT3 Blockade by JAK Inhibitor SHR0302 Attenuates Inflammatory Responses of Adjuvant-Induced Arthritis Rats and Decreases Th17 and Total B Cells. Joint Bone Spine. 2016 Oct;83(5):525-32.

[2]. Targeted Blockade of JAK/STAT3 Signaling Inhibits Proliferation, Migration and Collagen Production as Well as Inducing the Apoptosis of Hepatic Stellate Cells. Int J Mol Med. 2016 Sep;38(3):903-11.

Ivarmacitinib (SHR0302) is a selective Janus kinase 1 (JAK1) inhibitor currently under investigation for its efficacy in treating various immune-inflammatory diseases. Although Ivarmacitinib has not yet received marketing approval, as of February 2022, clinical trials are underway or completed to evaluate its use in atopic dermatitis, ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, graft-versus-host disease, vitiligo, ulcerative colitis, alopecia areata, and primary membranous nephropathy. Ivarmacitinib is an oral Janus-associated kinase 1 (JAK1) inhibitor with potential antitumor activity. After oral administration, Ivarmacitinib binds to JAK1 and inhibits its activity, thereby blocking JAK-dependent signaling. This may lead to the suppression of the proliferation of JAK1-overexpressing tumor cells. The JAK-STAT (signal transducer and activator of transcription) signaling pathway is a major mediator of cytokine activity and is often abnormally regulated in various tumor cell types. Furthermore, JAK1 is likely a major driver of STAT3 phosphorylation and signal transduction, while STAT3 plays a crucial role in tumor transformation, anti-apoptosis, tumor angiogenesis, metastasis, immune escape, and treatment resistance. Mechanism of Action Autoimmune inflammatory diseases are thought to result from the complex interactions of genetic, microbiome, and environmental factors, ultimately leading to dysregulation of T and B cell activity against the host. Therefore, therapeutic interventions aim to inhibit T cell activity and/or block cytokine activity. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a particularly promising therapeutic target, as its dysregulation is associated with a variety of immune diseases. In short, the JAK-STAT signaling pathway plays a vital role in the transmission of signals from cell membrane receptors to the cell nucleus and is essential for the transcription of various cytokines and growth factors, including those responsible for regulating innate and adaptive immune responses. The JAK family is a class of non-receptor tyrosine kinases, including JAK1, JAK2, JAK3, and TYK2, each containing multiple distinct domains and performing different functions. Ivarmacitinib is a highly selective JAK1 inhibitor. JAK1 regulates various cytokines such as IL-4, IL-5, IL-13, and IFN-γ, while Ivarmacitinib does not inhibit JAK2, thereby reducing the risk of adverse reactions such as anemia and neutropenia. By inhibiting this pathway, Ivarmacitinib may help prevent immune dysregulation that leads to various inflammatory diseases, including atopic dermatitis and rheumatic diseases such as rheumatoid arthritis.

C18H22N8O2S

414.4847

414.16

C, 52.16; H, 5.35; N, 27.03; O, 7.72; S, 7.73

1445987-21-2

1445987-21-2;1639419-51-4 (sulfate);1639419-53-6 (HCl);

71622431

Off-white to light yellow solid powder

2.3

2

8

4

29

600

2

CN(C1C[C@@H]2CN(C[C@@H]2C1)C(=O)NC3=NC(=NS3)OC)C4=NC=NC5=C4C=CN5

DNBCBAXDWNDRNO-FOSCPWQOSA-N

InChI=1S/C18H22N8O2S/c1-25(15-13-3-4-19-14(13)20-9-21-15)12-5-10-7-26(8-11(10)6-12)18(27)23-17-22-16(28-2)24-29-17/h3-4,9-12H,5-8H2,1-2H3,(H,19,20,21)(H,22,23,24,27)/t10-,11+,12?

(3aS,6aR)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide

SHR0302 SHR-0302 SHR 0302

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)

DMSO : ~31.25 mg/mL (~75.40 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.02 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 20.8 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: ≥ 2.08 mg/mL (5.02 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 20.8 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: ≥ 2.08 mg/mL (5.02 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 20.8 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.)