Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634
Journal of Medicinal Chemistry2014Vol. 57(22), pp. 9323–9342
Citations Over TimeTop 10% of 2014 papers
Christel Menet, Stephen R. Fletcher, Guy Van Lommen, Raphaël Geney, Javier Blanc, Koen Smits, Nolwenn Jouannigot, Pierre Deprez, Ellen M. van der Aar, Philippe Clément-Lacroix, L. Lepescheux, René Galien, Béatrice Vayssière, L Nelles, Thierry Christophe, Reginald Brys, Muriel Uhring, Fabrice Ciesielski, Luc Van Rompaey
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).
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