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| Product Name: | Filgotinib | | Synonyms: | GPLG0634;GLPG0634;SYN1158;CyclopropanecarboxaMide, N-[5-[4-[(1,1-dioxido-4-thioMorpholinyl)Methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]-;GLPG0634 (analog);N-[5-[4-[(1,1-Dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide;N-(5-(4-((1,1-Dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide;Filgotinib (GLPG0634) | | CAS: | 1206161-97-8 | | MF: | C21H23N5O3S | | MW: | 425.5 | | EINECS: | | | Product Categories: | Inhibitors;API;1206161-97-8 | | Mol File: | 1206161-97-8.mol |  |
| | Filgotinib Chemical Properties |
| Melting point | 229 - 231°C | | density | 1.51±0.1 g/cm3(Predicted) | | storage temp. | -20°C | | solubility | Soluble in DMSO (15 mg/ml with warming) | | form | solid | | pka | 8.04±0.20(Predicted) | | color | Off-white | | Stability: | Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month. |
| | Filgotinib Usage And Synthesis |
| Description | Filgotinib (GLPG0634) is a selective JAK1 inhibitor with IC50 of 10 nM, 28 nM, 810 nM, and 116 nM for JAK1, JAK2, JAK3, and TYK2, respectively. | | 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. | | Description | Filgotinib is a JAK1 inhibitor (IC50 = 10 nM). It is selective for JAK1 over JAK3 (IC50 = 810 nM) but also inhibits JAK2 and tyrosine kinase 2 (Tyk2; IC50s = 28 and 116 nM, respectively), as well as Abl, FLT1, -3, and -4, FMS, Mer, and TBK1 activity by greater than 35% in a panel of 177 tyrosine kinases at 1 μM. Filgotinib inhibits IL-6-induced phosphorylation of STAT1 in CD4+ T cells with an IC50 value of 629 nM in isolated human whole blood. 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. | | Uses | GLPG-0634 (Filgotinib) is a potent, selective JAK1 inhibitor. Used as an anti-inflammatory agent, it reduces levels of inflammatory cytokines in the bones and tissue of mammals. | | 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 infection
- urinary 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 |
| | Filgotinib Preparation Products And Raw materials |
| Raw materials | 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine-->Thiomorpholine-1,1-dioxide-->Ethyl (6-BroMo-pyridin-2-ylaMino)carbonothioylcarbaMate-->4-(Bromomethyl)benzeneboronic acid pinacol ester-->4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]thiomorpholine 1,1-dioxide-->cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide-->[1,2,4]Triazolo[1,5-a]pyridin-2-amine, 5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl]--->N-(5-(4-(bromomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide-->THIOMORPHOLINE 1,1-DIOXIDE HYDROCHLORIDE-->N-(5-(4-(hydroxymethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide-->2-Amino-6-bromopyridine-->Cyclopropanecarbonyl Chloride |
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