pha-767491 and Inflammation

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.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Crystallography, X-Ray; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Models, Molecular; Protein Serine-Threonine Kinases; Pyridines; Pyrroles; Rats; Structure-Activity Relationship; Tumor Necrosis Factor-alpha; U937 Cells