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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.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Mar 15; Vol. 22 (6), pp. 2266-70. Date of Electronic Publication: 2012 Jan 31. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 22342143
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.01.077