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GLPG0634

Names

[ CAS No. ]:
1206161-97-8

[ Name ]:
GLPG0634

[Synonym ]:
N-[5-[4-[(1,1-Dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
Filgotinib
N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
cyclopropanecarboxylic acid {5-[4-((1,1-dioxo-1-thimorpholin-4-yl)methyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide
Cyclopropanecarboxamide, N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]-
G146034
N-(5-{4-[(1,1-Dioxido-4-thiomorpholinyl)methyl]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
cyclopropanecarboxylic acid {5-[ 4-(1,1-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide
GLPG0634
UNII-3XVL385Q0M

Biological Activity

[Description]:

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.

[Related Catalog]:

Signaling Pathways >> Epigenetics >> JAK
Signaling Pathways >> JAK/STAT Signaling >> JAK
Signaling Pathways >> Stem Cell/Wnt >> JAK
Research Areas >> Cancer

[Target]

JAK1:10 nM (IC50)

JAK2:28 nM (IC50)

Tyk2:116 nM (IC50)

JAK3:810 nM (IC50)


[In Vitro]

GLPG0634 dose-dependently inhibits the differentiation of Th2 cells mediated by IL-4, a cytokine that signals through JAK1 and JAK3. GLPG0634 also inhibits Th1 differentiation with similar potencies of 1 μM or lower[1]. GLPG0634 does not inhibit JAK2 homodimer-mediated signaling induced by EPO or PRL (IC50 > 10 μM)[2].

[In Vivo]

GLPG0634 (3, 10, 30 mg/kg, p.o.) dose-dependently prevents disease progression in the therapeutic rat CIA model. GLPG0634 (50 mg/kg, o.p.) protects bone and cartilage from degradation, effectively reduces infiltration of T cells (CD3+ cells) and macrophages (F4/80+ cells) in the paw, and decreases the serum levels of all cytokines and chemokines measured, including IL-6, IP-10, XCL1, and MCP-1[1]. GLPG0634 (0.1 and 0.3 mg/kg) shows efficacy in the rat CIA model[2].

[Kinase Assay]

Recombinant JAK1, TYK2, JAK2, and JAK3 are used to develop activity assays in 50 mM HEPES (pH 7.5), 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, and 0.01% Tween 20. The amount of JAK protein is determined per aliquot, maintaining initial velocity and linearity over time. The ATP concentration is equivalent to 4× the experimental Km value and the substrate concentration (ULight-conjugated JAK-1(Tyr1023) peptide) corresponds to the experimentally determined Km value. After 90 min incubation at room temperature (RT), the amount of phosphorylated substrate is measured by addition of 2 nM europium-anti-phosphotyrosine Ab and 10 mM EDTA in Lance detection buffer. Compound IC50 values are determined by preincubating the enzyme with compound at RT for 60 min, prior to the addition of ATP.

[Animal admin]

GLPG0634 is orally dosed as a single esophageal gavage at 5 mg/kg (dosing volume of 5 mL/kg) and i.v. dosed as a bolus via the caudal vein at 1 mg/kg (dosing volume of 5 mL/kg). In the rat study, each group consists of three rats and blood samples are collected via the jugular vein. In the mouse study, each group consists of 21 mice (n=3/time point) and blood samples are collected by intracardiac puncture under isoflurane anesthesia. Lithium heparin is used as anticoagulant and blood is taken at 0.05, 0.25, 0.5, 1, 3, 5, and 8 h (i.v. route) and 0.25, 0.5, 1, 3, 5, 8, and 24 h (by mouth).

[References]

[1]. Van Rompaey L, et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol. 2013, 191(7), 3568-3577.

[2]. Menet CJ, et al. Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634. J Med Chem. 2014 Nov 17.


[Related Small Molecules]

Baricitinib | Upadacitinib | Pacritinib | CYT387 | AZD1480 | Fedratinib(SAR302503,TG101348) | WP1066 | CHZ868 | AT9283 | Itacitinib | cerdulatinib | LY2784544 | SB1317 | Peficitinib | Pyridone 6

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Molecular Formula ]:
C21H23N5O3S

[ Molecular Weight ]:
425.504

[ Exact Mass ]:
425.152161

[ PSA ]:
108.28000

[ LogP ]:
0.79

[ Index of Refraction ]:
1.748

[ Storage condition ]:
2-8°C

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds