Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634
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- 作者：Christel J. Menet ; Stephen R Fletcher ; Guy Van Lommen ; Raphael Geney ; Javier Blanc ; Koen Smits ; Nolwenn Jouannigot ; Pierre Deprez ; Ellen M. van der Aar ; Philippe Clement-Lacroix ; Li锚n Lepescheux ; Ren茅 Galien ; B茅atrice Vayssiere ; Luc Nelles ; Thierry Christophe ; Reginald Brys ; Muriel Uhring ; Fabrice Ciesielski ; Luc Van Rompaey
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：November 26, 2014
- 年：2014
- 卷：57
- 期：22
- 页码：9323-9342
- 全文大小：797K
- ISSN：1520-4804
文摘
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鈥檚 disease (CD).