1. 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.
- Author
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Andrews MJ, Clase JA, Bar G, Tricarico G, Edwards PJ, Brys R, Chambers M, Schmidt W, MacLeod A, Hirst K, Allen V, Birault V, Le J, Harris J, Self A, Nash K, and Dixon G
- Subjects
- Animals, Antirheumatic Agents pharmacokinetics, Antirheumatic Agents pharmacology, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid enzymology, Binding Sites, High-Throughput Screening Assays, Humans, Hydrogen Bonding, Imidazoles pharmacokinetics, Imidazoles pharmacology, Intracellular Signaling Peptides and Proteins metabolism, Models, Molecular, Protein Binding, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Rats, Small Molecule Libraries, Structure-Activity Relationship, Antirheumatic Agents chemical synthesis, Imidazoles chemical synthesis, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles chemical synthesis
- 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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