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

[21] Analysis Of The JAK1 Selectivity Of GLPG0634 and Its Main Metabolite In Different Species, Healthy Volunteers and Rheumatoid Arthritis Patients
Galien, Rene
Vayssiere, Beatrice
de Vos, Steve
Auberval, Marielle
Vandeghinste, Nick
Dupont, Sonia
Clement-Lacroix, Philippe
Delerive, Philippe
Vanhoutte, Frederic
Brys, Reginald
Van der Aa, Annegret
Van Rompaey, Luc
van't Klooster, Gerben
ARTHRITIS AND RHEUMATISM, 2013, 65 : S209 - S210
[22] Author’s Reply to Srinivas: “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection”
Florence Namour
Clinical Pharmacokinetics, 2015, 54 : 1297 - 1298
[23] Author's Reply to Srinivas: "Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection"
Namour, Florence
CLINICAL PHARMACOKINETICS, 2015, 54 (12) : 1297 - 1298
[24] Exploration of GLPG0634, the First Selective JAK1 Inhibitor, in Inflammatory Bowel Disease Is Supported by Early Clinical Results and Mouse DSS-Colitis Data
Galien, Rene
Merciris, Didier
Vanhoutte, Frederic P.
Delachaume, Carole
Namour, Florence S.
Vayssiere, Beatrice
Van der Aa, Annegret
Brys, Reginald
van't Klooster, Gerben A.
GASTROENTEROLOGY, 2014, 146 (05) : S49 - S49
[25] Analysis Of The JAK1 Selectivity Of GLPG0634 and Its Main Metabolite In Different Species, Healthy Volunteers and Rheumatoid Arthritis Patients.
Fleischmann, R.
Schiff, M.
Weinblatt, M. E.
Maldonado, M.
Massarotti, E.
Yazici, Y.
ARTHRITIS AND RHEUMATISM, 2013, 65 : S209 - S209
[26] IDENTIFICATION OF A GENE SIGNATURE AND RESPONSE BIOMARKERS IN CIRCULATING LEUKOCYTES OF RA PATIENTS AFTER TREATMENT WITH THE JAK1-SELECTIVE INHIBITOR FILGOTINIB (GLPG0634)
Ongenaert, M.
Dupont, S.
Vayssiere, B.
Meuleners, L.
Brys, R.
Galien, R.
ANNALS OF THE RHEUMATIC DISEASES, 2015, 74 : 1068 - 1068
[27] Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective As Monotherapy in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study
Kavanaugh, Arthur
Ponce, Lucia
Cseuz, Regina
Reshetko, Olga
Stanislavchuk, Mykola A.
Greenwald, Maria
Van der Aa, Annegret
Vanhoutte, Frederic
Tasset, Chantal
Harrison, Pille
ARTHRITIS & RHEUMATOLOGY, 2015, 67
[28] Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study
Westhovens, R.
Alten, Rieke
Pavlova, Dace
Enriquez-Sosa, Favio
Mazur, Minodora
Greenwald, Maria
Van der Aa, Annegret
Vanhoutte, Frederic
Tasset, Chantal
Harrison, Pille
ARTHRITIS & RHEUMATOLOGY, 2015, 67
[29] The Effect of Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor on Patient-Reported Outcomes: Results from Two 24-Week Phase 2B Dose Ranging Studies
Genovese, Mark C.
Westhovens, R.
Kavanaugh, Arthur
Meuleners, Luc
Van der Aa, Annegret
Harrison, Pille
Tasset, Chantal
ARTHRITIS & RHEUMATOLOGY, 2016, 68
[30] Identification of azabenzimidazoles as potent JAK1 selective inhibitors
Vasbinder, Melissa M.
Alimzhanov, Marat
Augustin, Martin
Bebernitz, Geraldine
Bell, Kirsten
Chuaqui, Claudio
Deegan, Tracy
Ferguson, Andrew D.
Goodwin, Kelly
Huszar, Dennis
Kawatkar, Aarti
Kawatkar, Sameer
Read, Jon
Shi, Jie
Steinbacher, Stefan
Steuber, Holger
Su, Qibin
Toader, Dorin
Wang, Haixia
Woessner, Richard
Wu, Allan
Ye, Minwei
Zinda, Michael
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2016, 26 (01) : 60 - 67

← 1 2 3 4 5 →