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J Med Chem. 2014 Nov 26;57(22):9323-42. doi: 10.1021/jm501262q. Epub 2014 Nov 17.

Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.

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Galapagos NV , Generaal de Wittelaan L11A3, 2800 Mechelen, Belgium.


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).

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