MAPKs include many serine-threonine kinases. One of the major MAPK cascades is p38 MAPKs. p38 MAPK can serve as a potential therapeutic target for the treatment of not only inflammatory diseases but also cancer. In addition, p38 MAPK plays an important role in key cellular processes related to inflammation and cancer. One of the first synthesized compounds against p38 MAPKs is SB 203580. SB 203580 inhibits p38 MAPK, nitric oxide production and inducible nitric oxide synthase in bovine cartilage-derived chondrocytes. Nowadays, SB 203580 acts as the literature standard for p38 kinase inhibitor (IC50=0.3–0.5 μM). In this study, researchers reported the synthesis of RWJ 67657. Especially, RWJ 67657 is a selective p38α and p38β inhibitor (IC50=1 and 11 μM, respectively).

RWJ 67657 displays no activity at p38γ and p38δ. Moreover, RWJ 67657 exhibits cardioprotective and anti-inflammatory activity in addition to being orally active. In particular, RWJ 67657 is approximately ten-fold more potent than SB 203580. RWJ-67657 inhibits the release of TNF-αby lipopolysaccharide-treated human peripheral blood mononuclear cells with an IC50 of 3 nM.

RWJ-67657 inhibits the release of TNF-α from peripheral blood mononuclear cells treated with the superantigen staphylococcal enterotoxin B with an IC50 of 13 nM. Besides, RWJ-67657 inhibits the enzymatic activity of recombinant p38α and p38β, but not p38γ or p38δ in vitro. Furthermore, RWJ 67657 has no significant activity against a variety of other enzymes. RWJ-67657 inhibits TNF-α production in lipopolysaccharide-injected mice (87% inhibition at 50 mg/kg) and in rats (91% inhibition at 25 mg/kg) after oral administration.

In a word, RWJ-67657 may have use as a treatment for inflammatory diseases.

Wadsworth SA, et al. RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exp Ther. 1999 Nov;291(2):680-7.