Imidazopyrimidines, Potent Inhibitors of p38 MAP Kinase.

The MAP kinase p38 is implicated in the release of the pro-inflammatory cytokines TNF-α and IL-1β. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn\u27s disease. A novel series of imidazopyrimidines have been discovered that potently inhibit p38 and suppress the production of TNF-α in vivo

Imidazopyrimidines, Potent Inhibitors of P38 MAP Kinase

The MAP kinase p38 is implicated in the release of the pro-inflammatory cytokines TNF-α and IL-1β. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn\u27s disease. A novel series of imidazopyrimidines have been discovered that potently inhibit p38 and suppress the production of TNF-α in vivo

Potent Inhibitors of the MAP Kinase p38

The MAP kinase p38 plays a key role in the biosynthesis of the inflammatory cytokines TNF-α and IL-1. We have developed a novel series of potent p38 inhibitors that could lead to new methods of treatment for inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease

RWJ 67657, a Potent, Orally Active Inhibitor of P38 Mitogen-Activated Protein Kinase

Tumor necrosis factor-α (TNF-α), a cytokine secreted by activated monocytes/macrophages and T lymphocytes, has been implicated in several disease states, including rheumatoid arthritis, inflammatory bowel disease, septic shock, and osteoporosis. Monocyte/macrophage production of TNF-α is dependent on the mitogen-activated protein kinase p38. RWJ 67657 (4-[4-(4- fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1- ol) inhibited the release of TNF-α by lipopolysaccharide (a monocyte stimulus)-treated human peripheral blood mononuclear cells with an IC50 of 3 nM, as well as the release of TNF-α from peripheral blood mononuclear cells treated with the superantigen staphylococcal enterotoxin B (a T cell stimulus), with an IC50 value of 13 nM. This compound was approximately 10- fold more potent than the literature standard p38 kinase inhibitor SB 203580 in all p38 dependent in vitro systems tested. RWJ 67657 inhibited the enzymatic activity of recombinant p38α and β, but not γ, or δ, in vitro and had no significant activity against a variety of other enzymes. In contrast, SB 203580 significantly inhibited the tyrosine kinases p56 lck and c-src (IC50 = 5 μM). RWJ 67657 did not inhibit T cell production of interleukin-2 or interferon-γ, and did not inhibit T cell proliferation in response to mitogens. RWJ 67657 inhibited 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. Based on these favorable biological properties, RWJ 67657 may have use as a treatment for inflammatory diseases