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 Tmax of ivarmacitinib is approximately one hour.

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Biological Half-Life
The half-life of ivarmacitinib following oral administration is 8.33 - 9.87 hours and increases slightly with increasing dosage.

[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 inhibitor of Janus kinase 1 (JAK1) under investigation for the treatment of various immuno-inflammatory conditions. While ivarmactinib has yet to receive marketing authorization, as of February 2022 clinical trials are ongoing or completed evaluating 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 orally available inhibitor of Janus-associated kinase 1 (JAK1), with potential antineoplastic activity. Upon oral administration, ivarmacitinib binds to and inhibits JAK1, thereby preventing JAK-dependent signaling. This may lead to an inhibition of cellular proliferation in 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 dysregulated in a variety of tumor cell types. Additionally, JAK1 may be a primary driver of STAT3 phosphorylation and signaling, which plays a role in neoplastic transformation, resistance to apoptosis, tumor angiogenesis, metastasis, immune evasion, and treatment resistance.

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Mechanism of Action
Autoimmune inflammatory diseases are thought to arise from a complex interplay of genetics, microbiota, and environmental factors that ultimately lead to dysregulated T- and B-cell activity against the host. Therapeutic interventions are therefore aimed at suppressing T-cell activity and/or blocking cytokine activity. A therapeutic target of particular interest is the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, the dysregulation of which has been implicated in a variety of immune disorders. Put simply, the JAK-STAT pathway plays a significant role in the transduction of signals from cell membrane receptors to the nucleus, and is essential for the transcription of a range of cytokines and growth factors, including those responsible for orchestrating innate and adaptive immune responses. The JAK family of non-receptor tyrosine kinases includes JAK1, JAK2, JAK3, and TYK2, each of which comprise several distinct domains and serve distinct functions. Ivarmacitinib is a highly selective inhibitor of JAK1 - which modulates IL-4, IL-5, IL-13, and IFN-γ, amongst other cytokines - while sparing inhibition of JAK2 in order to decrease the risk of adverse effects like anemia and neutropenia. By inhibiting this pathway, ivarmacitinib may help to prevent the immune dysregulation responsible for a number of inflammatory conditions, including atopic dermatitis and rheumatologic diseases (e.g. 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.)