Filgotinib
Grundinformationen
- CAS
1206161-97-8- Standard-SMILES
O=C(Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1)C1CC1- InChIKey
RIJLVEAXPNLDTC-UHFFFAOYSA-N- Summenformel
- C21H23N5O3S
- Durchschnittliche Molmasse
- 425,5 g/mol
- Monoisotopische Masse
- 425,15216079
Überblick
Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, and inflammatory disease that causes synovial joint symptoms and can limit range of motion in severe cases. The disease is associated with extra-articular manifestations, progressive disability, and comorbidities including cardiovascular disease and mental disorders. 50-70% of patients with RA are unable to achieve sustained clinical remission despite the availability of several treatments including disease-modifying anti-rheumatic drugs (DMARDS) like [methotrexate], interleukin-6 (IL-6) blockers, and tumor necrosis factor (TNF) inhibitors. New therapeutic developments target other inflammatory pathways implicated in RA including the Janus kinase (JAK) signaling pathway as seen with filgotinib. There are four JAK subtypes which include JAK1, JAK2, JAK3, and tyrosine kinase 2. Non-selective JAK inhibitors like [tofacitinib] target JAK1 and JAK3 subtypes with minimal activity at JAK2. In contrast, the newly approved filgotinib is a highly selective JAK1 inhibitor. JAK2 and JAK3 play important roles in both immune and hematologic functions; therefore, selectivity for JAK1 aims to improve the safety profile of filgotinib while maintaining clinical efficacy. Filgotinib is currently reserved for patients who cannot tolerate DMARDs, or who have been unable to achieve remission in response to one or more DMARDs.
Namen und Bezeichner
- Bevorzugter Name
- Filgotinib
- IUPAC
- N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
- Englischer Name
- Filgotinib
- Summenformel
- C21H23N5O3S
- Molmasse
- 425.5
Namen und Synonyme
Filgotinib1206161-97-8GLPG-0634N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide3XVL385Q0MGS-6034 FREE BASEGLPG 0634G146034G-146034DTXSID80152935N-(5-{4-[(1,1-dioxo-1lambda6-thiomorpholin-4-yl)methyl]phenyl}-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamidefilgotinibum
Weitere Namen anzeigen
GPLG0634GLPG634SYN1158CS-1083FeigotiniGLPG0634 >=95%GLPG0634 (analog)
N-(5-(4-((1,1-dioxo-1,4-thiazinan-4-yl)methyl)phenyl)-(1,2,4)triazolo(1,5-a)pyridin-2-yl)cyclopropanecarboxamideN-(5-(4-((1,1-dioxo-1lambda6-thiomorpholin-4-yl)methyl)phenyl)-(1,2,4)triazolo(1,5-a)pyridin-2-yl)cyclopropanecarboxamideRefChem:921607DTXCID70754261206101-20-3GLPG0634Filgotinib (GLPG0634)N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide
Datenbank-Bezeichner
Eigenschaften
Berechnete Struktureigenschaften
- XLogP
- 1,4
- Polarare Oberfläche (TPSA)
- 105 Ų
- H-Brücken-Donoren
- 1
- H-Brücken-Akzeptoren
- 6
- Frei drehbare Bindungen
- 5
- Schwere Atome
- 30
- Formalladung
- 0
- Komplexität
- 715
Experimentelle und physikochemische Eigenschaften
Human Drugs
Breast Feeding; Lactation; Milk, Human; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Janus Kinase Inhibitors; JAK Inhibitors
EMA approved medicines: Human medicine
Physikochemische Eigenschaften
- Schmelzpunkt
- 229 · 229 - 231°C
- Dichte
- 1.51 · 1.51±0.1 g/cm3(Predicted)
- storage temp.
- -20 °C · -20°C
- Löslichkeit
- Soluble in DMSO (15 mg/ml with warming)
- pka
- 8.04 · 8.04±0.20(Predicted)
- Aggregatzustand
- solid
- Farbe
- Off-white
- Stabilität
- 2 years · Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
- InChI
- InChI=1S/C21H23N5O3S/c27-20(17-8-9-17)23-21-22-19-3-1-2-18(26(19)24-21)16-6-4-15(5-7-16)14-25-10-12-30(28,29)13-11-25/h1-7,17H,8-14H2,(H,23,24,27)
Sicherheit und Regulatorisches
GHS-Klassifizierung
GHS Classification
Warning
H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]
P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)
The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.
Gefahrenhinweise
Hazard Classes and CategoriesSkin Irrit. 2 (100%)
Toxikologische Informationen
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
Sicherheitsdaten
- hs_code
- 2921309990
Chemie und Industrie
Pharmakologische Informationen
ATC Code
L - Antineoplastic and immunomodulating agents
QL - Antineoplastic and immunomodulating agents
Protein BindingApproximately 55-59% of filgotinib is protein-bound, while 39-44% of the active metabolite GS-829845 is protein-bound.
Pharmacodynamics
In addition to targeted Janus kinase (JAK) 1 inhibition, filgotinib targets pro-inflammatory cytokine signalling by inhibiting IL-6 induced STAT1 phosphorylation. Serum C-reactive protein levels are also reduced in response to filgotinib administration.
Mechanism of Action
There are four Janus kinase (JAK) enzymes including JAK1, JAK2, JAK3, and tyrosine kinase 2. JAK1 mediates inflammatory cytokine signaling, while JAK2 and JAK3 are important components of hematologic and immune functions. Filgotinib selectively inhibits JAK1 and is for example nearly 30-fold more selective for JAK1 compared to JAK2. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is implicated in several inflammatory pathologies and has been found to be continuously active in patients who have RA. Sustained activation of this pathway contributes to aberrant processes which lead to disease progression including elevated levels of matrix metalloproteinases (MMPs) and reduced cell apoptosis in RA affected synovial tissues. Filgotinib acts on the JAK-STAT pathway by selectively inhibiting JAK1 phosphorylation and preventing STAT activation, which ultimately results in reduced proinflammatory cytokine signaling.
Biological Half-LifeThe half-life of filgotinib is estimated to be 7 hours, while the half-life of its active metabolite GS-829845 is estimated to be 19 hours.
Metabolism/Metabolites
Carboxylesterase enzymes are involved in the metabolism of filgotinib. The carboxylesterase 2 (CES2) isoform is chiefly responsible for metabolizing filgotinib to its major metabolite, GS-829845. Although carboxylesterase 1 (CES1) plays a less prominent role in the biotransformation of filgotinib, in vitro studies have demonstrated that CES1 will partially compensate in the event of CES2 saturation. GS-829845 is thus far the only major circulating metabolite to have been identified.
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