We wish to report our initial findings that RWJ 68354 (1) is a potent inhibitor of p38 kinase in vitro (IC50 9 nM) and in vivo (ED50 <10 mg/kg po), and is highly selective across a panel of assays. We have shown 1 to be a potent inhibitor of cellular p38 kinase activity (9 nM), LPS-stimulated TNF-R/IL-1β production from human PBMCs (6.3 nM/26 nM), and LPS-induced TNF-R production in mice (ED50 <10 mg/kg) and in rats (ED50 <25 mg/kg). The compound directly inhibits natural activated p38 and partially activated recombinant p38 kinase, is more potent than the literature standard 4 in both in vitro and in vivo assays, and is orally active. Thus, 1 is a promising candidate for further preclinical evaluation.