PH-797804 is a potent, highly selective and ATP-competitive p38α/p38β MAPK inhibitor with IC50 of 2.3 nM (p38α). PH-797804 exhibits significant inhibition of TNFα release in hPBMC with IC50 of 3.4 nM. PH-797804 is a readily reversible inhibitor of the alpha isoform of human p38 MAP kinase with Ki of 5.8 nM. PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E(2) in human monocyte and synovial fibroblast cell systems. PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis.
