title: Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis.
abstract: MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.
authors.affiliation: Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Belgium. martin.andrews@glpg.com
authors.forename: Martin J I
authors.initials: MJ
authors.lastname: Andrews
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Clase
authors.forename: Gregory
authors.initials: G
authors.lastname: Bar
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tricarico
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Edwards
authors.forename: Reginald
authors.initials: R
authors.lastname: Brys
authors.forename: Mark
authors.initials: M
authors.lastname: Chambers
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmidt
authors.forename: Angus
authors.initials: A
authors.lastname: MacLeod
authors.forename: Kim
authors.initials: K
authors.lastname: Hirst
authors.forename: Vivienne
authors.initials: V
authors.lastname: Allen
authors.forename: Veronique
authors.initials: V
authors.lastname: Birault
authors.forename: Joelle
authors.initials: J
authors.lastname: Le
authors.forename: John
authors.initials: J
authors.lastname: Harris
authors.forename: Andrew
authors.initials: A
authors.lastname: Self
authors.forename: Kevin
authors.initials: K
authors.lastname: Nash
authors.forename: Graham
authors.initials: G
authors.lastname: Dixon
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D001665:Binding Sites; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D018501:Antirheumatic Agents; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D054852:Small Molecule Libraries; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases