Journal of Medicinal Chemistry · 2007 · 170 citations · 6 references
MedicineMedicinal ChemistryPharmacologyInflammationRheumatologyStructure-activity RelationshipsAnti-inflammatory PharmacologyCytokine BiologyInflammatory ArthritisInflammatory SignalingRheumatoid ArthritisStructure-activity Relationship AnalysisAnti-inflammatory TherapeuticsKinase Inhibitor ProfilingKinase InhibitorsKinase Selectivity ProfilingMitogen-activated Protein Kinase KinaseRheumatoid Arthritis PharmacotherapyRheumatoid Arthritis TherapySelectivity
A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFalpha production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.
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MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis
Alexey Kotlyarov, Armin Neininger, Carola Schubert et al. · Nature Cell Biology · 1999 · 767 citations