Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634

被引：108

作者：

Menet, Christel J. ^{[1
]}

Fletcher, Stephen R. ^{[2
]}

Van Lommen, Guy ^{[1
]}

Geney, Raphael ^{[3
]}

Blanc, Javier ^{[1
]}

Smits, Koen ^{[1
]}

Jouannigot, Nolwenn ^{[1
]}

Deprez, Pierre ^{[3
]}

van der Aar, Ellen M. ^{[1
]}

Clement-Lacroix, Philippe ^{[3
]}

Lepescheux, Lien ^{[3
]}

Galien, Rene ^{[3
]}

Vayssiere, Beatrice ^{[3
]}

Nelles, Luc ^{[1
]}

Christophe, Thierry ^{[1
]}

Brys, Reginald ^{[1
]}

Uhring, Muriel ^{[4
]}

Ciesieski, Fabrice ^{[4
]}

Van Rompaey, Luc ^{[1
]}

机构：

[1] Galapagos NV, B-2800 Mechelen, Belgium

[2] BioFocus, Saffron Walden CB10 1XL, Essex, England

[3] Galapagos SASU, F-93230 Romainville, France

[4] NovAliX, F-67405 Illkirch Graffenstaden, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 22期

关键词：

INFLAMMATORY DISEASES; RHEUMATOID-ARTHRITIS; CYTOKINE RECEPTORS; RESTRICTED ROLE; DISCOVERY; RESPONSES; POTENT;

D O I：

10.1021/jm501262q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Crohns disease (CD).

引用

页码：9323 / 9342

页数：20

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