1206161-97-8 Usage
Description
Filgotinib (GLPG0634) is a selective JAK1 inhibitor with IC50 values of 10 nM for JAK1, 28 nM for JAK2, 810 nM for JAK3, and 116 nM for TYK2. It is a potent and selective inhibitor of JAK1, showing a higher selectivity for JAK1 over JAK3. Filgotinib also inhibits other tyrosine kinases such as Abl, FLT1, -3, and -4, FMS, Mer, and TBK1 by more than 35% in a panel of 177 tyrosine kinases at 1 μM. It effectively inhibits IL-6-induced phosphorylation of STAT1 in CD4+ T cells with an IC50 value of 629 nM in isolated human whole blood.
Uses
Used in Anti-Inflammatory Applications:
Filgotinib (GLPG0634) is used as an anti-inflammatory agent in the treatment of various inflammatory conditions. It reduces levels of inflammatory cytokines in the bones and tissue of mammals, providing relief from inflammation and associated symptoms.
Used in Autoimmune Diseases:
Filgotinib is used as a therapeutic agent for autoimmune diseases, such as rheumatoid arthritis. It reduces hind paw macrophage and T cell infiltration and bone erosion in a rat model of collagen-induced arthritis when administered at doses ranging from 0.1 to 30 mg/kg per day for 15 days.
Used in Pharmaceutical Industry:
Filgotinib (GLPG0634) is used as a selective JAK1 inhibitor in the pharmaceutical industry for the development of targeted therapies for various inflammatory and autoimmune diseases. Its high selectivity and potency make it a valuable compound for research and drug development.
Used in Research Applications:
Filgotinib is used as a research tool in the study of JAK-STAT signaling pathways and the role of JAK1 in various cellular processes. It helps researchers understand the molecular mechanisms underlying inflammation and autoimmune diseases, leading to the development of novel therapeutic strategies.
In vitro
In cell lines, GLPG0634 inhibits IL-2- and IL-4-induced JAK1/JAK3/γc signaling and IFN-αB2-induced JAK1/TYK2 type II receptor signaling with IC50 ranged from 150 to 760 nM. GLPG0634 shows higher selectivity for JAK/STAT signaling involving JAK1 than JAK2 kinase in a cellular context. Besides, GLPG0634 also inhibits the differentiation of Th1, Th2, and Th17 cells.
In vivo
Following oral administration, the absolute bioavailability is moderate in rats (45%) and high in mice (～100%). Filgotinib (30 mg/kg daily (Rats); 50 mg/kg twice daily (Mice)) dose-dependently reduces inflammation, cartilage, and bone degradation in the CIA model in rats and mice. Filgotinib (GLPG0634) in DSS-treated mice demonstrates that inhibition of JAK1 is sufficient for achieving strong efficacy in pre-clinical mouse model, correlated to the inhibition of STAT3 phosphorylation in the inflamed colon.
Mechanism of action
Filgotinib acts on the JAK-STAT pathway by selectively inhibiting JAK1 phosphorylation and preventing STAT activation, which ultimately results in reduced proinflammatory cytokine signaling.
Side effects
feeling sick (nausea)upper respiratory tract infectionurinary tract infection.dizziness.
Synthesis
The synthesis of?Filgotinib is as follows:With cyclopropanyl chloride in an amidated reaction in a system consisting of N-methylmorpholine and 1,4-dioxane,The amidation reaction time was 4 h,The amidation reaction temperature was 50 ° C,The molar ratio of the intermediate (III), cyclopropanyl chloride, N-methylmorpholine and 1,4-dioxane was 1: 2.8: 2.5:TLC plate to determine the reaction is completed, cooled to room temperature,Adding methylene chloride and water, separating the organic phase with water,Then washed with brine, dried over magnesium sulfate,Evaporated to dryness and the residue was purified over a silica gel column [elution solvent: ethyl acetate / n-hexane (3: 7 v / v)To obtain a solid yellowish solid,That is, Filgotinib, yield 91.2%.
References
Menet et al. (2014), Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634; Med. Chem., 57 9323
Rompaey et al. (2013), Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases; Immunol., 191 3568
Kavanaugh et al. (2017), Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomized dose-finding study (DARWIN 2); Rheum. Dis., 76 1009
Wang et al. ?(2019), Oncostatin M inhibits differentiation of rat stem Leydig cells in vivo and in vitro; J. Cell. Mol. Med., 23 426
Check Digit Verification of cas no
The CAS Registry Mumber 1206161-97-8 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,0,6,1,6 and 1 respectively; the second part has 2 digits, 9 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 1206161-97:
(9*1)+(8*2)+(7*0)+(6*6)+(5*1)+(4*6)+(3*1)+(2*9)+(1*7)=118
118 % 10 = 8
So 1206161-97-8 is a valid CAS Registry Number.
1206161-97-8Relevant articles and documents
NOVEL PROCESS FOR THE PREPARATION OF FILGOTINIB AND INTERMEDIATES THEREOF
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, (2020/10/20)
The present invention relates to a novel process for the preparation of filgotinib or a pharmaceutically acceptable salt and intermediates thereof which avoid Suzuki coupling reaction. (I)
PROCESSES FOR THE PREPARATION OF FILGOTINIB
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, (2020/03/09)
The present invention relates to processes for the preparation of Filgotinib. The present invention relates to novel processes for the preparation of filgotinib. The present invention also relates to novel intermediates for the preparation of filgotinib.
[1,2,4]triazol[1,5-a]pyridine compound as well as preparation method and medical application thereof
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, (2018/03/24)
The invention relates to a [1,2,4]triazol[1,5-a] pyridine compound as well as a preparation method and medical application thereof. Particularly, the invention relates to the compound shown in a general formula I, the preparation method of the compound, a
