Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634

被引：101

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

共 50 条

[41] Reduction of tissue pSTAT3 in Crohn's disease patients treated with filgotinib (GLPG0634, GS-6034), a JAK1-selective inhibitor
Vermeire, S.
De Hertogh, G.
Chen, G.
French, D.
Huntzicker, E.
Van der Aa, A.
Van Kaem, T.
Harrison, P.
Tasset, C.
Galien, R.
Pan, Y.
Feagan, B.
Sandborn, W.
JOURNAL OF CROHNS & COLITIS, 2017, 11 : S20 - S21
[42] Treatment of Rheumatoid Arthritis Patients with the JAK1-Selective Inhibitor GLPG0634 Reverses an Arthritis-Specific Blood Gene Signature to Healthy State.
Ongenaert, Mate
Dupont, Sonia
Vayssiere, Beatrice
Brys, Reginald
Van Rompaey, Luc
Menet, Christel
Galien, Rene
ARTHRITIS & RHEUMATOLOGY, 2014, 66 : S657 - S658
[43] JAK1 selective inhibitors for the treatment of spondyloarthropathies
White, Jonathan P. E.
Coates, Laura C.
RHEUMATOLOGY, 2021, 60 : II39 - II44
[44] JAK1 selective inhibitors for the treatment of spondyloarthropathies
White, Jonathan P. E.
Coates, Laura C.
RHEUMATOLOGY, 2021, 60 (SUPPL 2) : ii39 - ii44
[45] Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)
Westhovens, R.
Taylor, P. C.
Alten, R.
Pavlova, D.
Enriquez-Sosa, F.
Mazur, M.
Greenwald, M.
Van der Aa, A.
Vanhoutte, F.
Tasset, C.
Harrison, P.
ANNALS OF THE RHEUMATIC DISEASES, 2017, 76 (06) : 998 - 1008
[46] FILGOTINIB (GLPG0634, GS-6034), A JAK-1 SELECTIVE INHIBITOR, SIGNIFICANTLY REDUCES GUT TISSUE PSTAT3 IN CROHN'S DISEASE PATIENTS
Sandborn, William J.
Feagan, Brian G.
De Hertogh, Gert
Chen, Guang
French, Dorothy M.
Huntzicker, Erik G.
Van der Aa, Annegret
Van Kaem, Tim
Harrison, Pille
Tasset, Chantal T.
Galien, Rene
Pan, Yang
Vermeire, Severine
GASTROENTEROLOGY, 2017, 152 (05) : S602 - S602
[47] The JAK1-Selective Inhibitor GLPG0634 Is Safe and Rapidly Reduces Disease Activity In Patients With Moderate To Severe Rheumatoid Arthritis; Results Of a 4-Week Dose Ranging Study
Tasset, Chantal
Harrison, Pille
Van der Aa, Annegret
Meuleners, Luc
Vanhoutte, Frederic
van 't Klooster, Gerben
ARTHRITIS AND RHEUMATISM, 2013, 65 : S1018 - S1018
[48] JAK1抑制剂GLPG0634在治疗类风湿性关节炎的Ⅱ期临床试验中获阳性结果
范鸣
药学进展, 2012, 36 (04) : 192 - 193
[49] Selective JAK1 inhibitors for the treatment of inflammatory bowel disease
Nielsen, Ole Haagen
Boye, Theresa Louise
Gubatan, John
Chakravarti, Deepavali
Jaquith, James B.
LaCasse, Eric C.
PHARMACOLOGY & THERAPEUTICS, 2023, 245
[50] Discovery and optimization of potent, selective, and orally bioavailable Jak1 inhibitors
Zak, Mark
Johnson, Adam
Van Abbema, Anne
Waszkowycz, Bohdan
Eigenbrot, Charles
Chang, Christine
Hurley, Christopher
Hanan, Emily
Kenny, Jane
Kulagowski, Janusz
DeVoss, Jason
Murray, Jeremy
Balazs, Mercedesz
Steffek, Micah
Koehler, Michael
Ghilardi, Nico
Chakravarty, Paroma
Lupardus, Patrick
Gibbons, Paul
Dragovich, Peter
Bergeron, Philippe
Pulk, Rebecca
Mendonca, Rohan
Savage, Scott
Labadie, Sharada
Gradl, Stefan
Ward, Stuart
Blair, Wade
Jia, Wei
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2012, 243

← 1 2 3 4 5 →