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

Martin J I Andrews; J Andrew Clase; Gregory Bar; Giovanni Tricarico; Paul J Edwards; Reginald Brys; Mark Chambers; Wolfgang Schmidt; Angus MacLeod; Kim Hirst; Vivienne Allen; Veronique Birault; Joelle Le; John Harris; Andrew Self; Kevin Nash; Graham Dixon

doi:10.1016/j.bmcl.2012.01.077

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

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2266-70. doi: 10.1016/j.bmcl.2012.01.077. Epub 2012 Jan 31.

Authors

Martin J I Andrews¹, J Andrew Clase, Gregory Bar, Giovanni Tricarico, Paul J Edwards, Reginald Brys, Mark Chambers, Wolfgang Schmidt, Angus MacLeod, Kim Hirst, Vivienne Allen, Veronique Birault, Joelle Le, John Harris, Andrew Self, Kevin Nash, Graham Dixon

Affiliation

¹ Galapagos NV, Generaal de Wittelaan L11 A3, 2800 Mechelen, Belgium. [email protected]

PMID: 22342143
DOI: 10.1016/j.bmcl.2012.01.077

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.

MeSH terms

Animals
Antirheumatic Agents / chemical synthesis*
Antirheumatic Agents / pharmacokinetics
Antirheumatic Agents / pharmacology
Arthritis, Rheumatoid / drug therapy
Arthritis, Rheumatoid / enzymology
Binding Sites
High-Throughput Screening Assays
Humans
Hydrogen Bonding
Imidazoles / chemical synthesis*
Imidazoles / pharmacokinetics
Imidazoles / pharmacology
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism
Models, Molecular
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology
Rats
Small Molecule Libraries
Structure-Activity Relationship

Substances

Antirheumatic Agents
Imidazoles
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyrazoles
Small Molecule Libraries
MAP-kinase-activated kinase 5
Protein Serine-Threonine Kinases