Abstract
Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry
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Animals
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Arthritis / drug therapy
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Chemistry, Pharmaceutical / methods*
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Collagen / chemistry
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Crohn Disease / drug therapy
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Crystallography, X-Ray
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Cytokines / metabolism
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Dimerization
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Disease Models, Animal
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Inhibitory Concentration 50
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Janus Kinase 1 / antagonists & inhibitors*
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Kinetics
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Phosphorylation
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Protein Kinase Inhibitors / chemistry*
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Pyridines / chemistry*
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Rats
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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Triazoles / chemistry*
Substances
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Cytokines
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GLPG0634
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Protein Kinase Inhibitors
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Pyridines
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Recombinant Proteins
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Triazoles
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Adenosine Triphosphate
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Collagen
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Janus Kinase 1