Filgotinib
[CAS# 1206161-97-8]

Identification

• Classification: Biochemical >> Inhibitor >> Tyrosine protein kinase/signal transducer and transcriptional activator inhibitor (JAK/STAT) >> JAK inhibitor
• Name: Filgotinib
• Synonyms: N-[5-[4-[(1,1-Dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
• Molecular Formula: C₂₁H₂₃N₅O₃S
• Molecular Weight: 425.51
• CAS Registry Number: 1206161-97-8
• EC Number: 858-411-3
• SMILES: C1CC1C(=O)NC2=NN3C(=N2)C=CC=C3C4=CC=C(C=C4)CN5CCS(=O)(=O)CC5

Properties

• Solubility: 1.8 g/L (water), DMSO
• Density: 1.51±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Index of Refraction: 1.748, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

Filgotinib is a novel small molecule drug developed as a selective inhibitor of Janus kinase 1 (JAK1), which plays a crucial role in the signaling pathways of various cytokines involved in inflammatory and immune responses. The discovery of filgotinib is rooted in the need for targeted therapies for autoimmune diseases, particularly rheumatoid arthritis (RA). Filgotinib's development began in the early 2010s, spearheaded by the pharmaceutical company Gilead Sciences in collaboration with Galapagos, a Belgian biotechnology company.

The compound was identified through a rigorous drug discovery process that involved screening various chemical entities for their ability to selectively inhibit JAK1 while minimizing off-target effects on other JAK family members. This selectivity is critical, as it enhances the therapeutic potential of the drug while reducing the risk of adverse effects associated with broader JAK inhibition. The synthesis of filgotinib involved a multi-step process, leading to a compound characterized by its specific structure that allows it to effectively bind to the JAK1 enzyme.

Filgotinib has shown promising results in clinical trials for several inflammatory conditions. In particular, its application in treating rheumatoid arthritis has garnered significant attention. Clinical studies have demonstrated that filgotinib can significantly reduce the signs and symptoms of RA, improving patient outcomes compared to traditional therapies. The drug's mechanism of action involves inhibiting the JAK1 enzyme, which in turn disrupts the downstream signaling of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). By doing so, filgotinib effectively mitigates the inflammatory processes that characterize autoimmune diseases.

In addition to rheumatoid arthritis, filgotinib is being investigated for its potential use in other autoimmune conditions, including ulcerative colitis and Crohn's disease. The versatility of filgotinib in targeting multiple inflammatory pathways makes it an attractive option for treating various inflammatory disorders. Ongoing clinical trials are exploring the efficacy and safety of filgotinib in these indications, with the aim of providing new therapeutic options for patients who have not responded well to existing treatments.

The approval of filgotinib for clinical use marks a significant advancement in the treatment landscape for autoimmune diseases. Its targeted mechanism of action represents a shift towards more personalized medicine, allowing for tailored therapeutic strategies based on individual patient needs. Additionally, filgotinib's favorable safety profile, combined with its efficacy, makes it a valuable addition to the repertoire of available treatments for chronic inflammatory conditions.

As research continues, filgotinib may offer new insights into the complex interplay of immune signaling pathways and their role in autoimmune diseases. Its discovery exemplifies the progress being made in the field of targeted therapies, with the potential to improve the quality of life for patients suffering from debilitating conditions.

References

2014. Triazolopyridine compounds as selective JAK1 inhibitors: from hit identification to GLPG0634. Journal of Medicinal Chemistry.
DOI: 10.1021/jm501262q

2017. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Annals of the Rheumatic Diseases.
DOI: 10.1136/annrheumdis-2016-210104

2024. Real‐World Comparative Effectiveness and Safety of Filgotinib and Upadacitinib for Ulcerative Colitis: A Multicentre Cohort Study. United European Gastroenterology Journal.
DOI: 10.1002/ueg2.12704