title: Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.
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).
authors.affiliation: Galapagos NV , Generaal de Wittelaan L11A3, 2800 Mechelen, Belgium.
authors.forename: Christel J
authors.initials: CJ
authors.lastname: Menet
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Fletcher
authors.forename: Guy
authors.initials: G
authors.lastname: Van Lommen
authors.forename: Raphael
authors.initials: R
authors.lastname: Geney
authors.forename: Javier
authors.initials: J
authors.lastname: Blanc
authors.forename: Koen
authors.initials: K
authors.lastname: Smits
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Jouannigot
authors.forename: Pierre
authors.initials: P
authors.lastname: Deprez
authors.forename: Ellen M
authors.initials: EM
authors.lastname: van der Aar
authors.forename: Philippe
authors.initials: P
authors.lastname: Clement-Lacroix
authors.forename: Liên
authors.initials: L
authors.lastname: Lepescheux
authors.forename: René
authors.initials: R
authors.lastname: Galien
authors.forename: Béatrice
authors.initials: B
authors.lastname: Vayssiere
authors.forename: Luc
authors.initials: L
authors.lastname: Nelles
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.forename: Reginald
authors.initials: R
authors.lastname: Brys
authors.forename: Muriel
authors.initials: M
authors.lastname: Uhring
authors.forename: Fabrice
authors.initials: F
authors.lastname: Ciesielski
authors.forename: Luc
authors.initials: L
authors.lastname: Van Rompaey
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003094:Collagen / Q000737:chemistry; D003424:Crohn Disease / Q000188:drug therapy; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D007700:Kinetics; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D016207:Cytokines; C584571:GLPG0634; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D014230:Triazoles; D000255:Adenosine Triphosphate; D003094:Collagen; D053613:Janus Kinase 1